Alpha-fluoroalkyl dihydrotetrabenazine imaging agents and probes

ABSTRACT

The present invention provides novel alpha-fluoroalkyl dihydrotetrabenazine compounds I 
                         
wherein R 1  is a C 1 -C 10  fluorinated aliphatic radical; R 2  is hydrogen or a C 1 -C 10  aliphatic radical; R 3  is hydrogen or a C 1 -C 10  aliphatic radical; and R 4  is a C 1 -C 10  aliphatic radical, a C 3 -C 10  cycloaliphatic radical, or a C 3 -C 10  aromatic radical. The alpha-fluoroalkyl dihydrotetrabenazine compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The alpha-fluoroalkyl dihydrotetrabenazine compounds are believed to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The alpha-fluoroalkyl dihydrotetrabenazine compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabled alpha-fluoroalkyl dihydrotetrabenazine compounds are useful as probes for the discovery of PET imaging agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part of U.S. patent applications, Ser. Nos. 11/947,215, and 11/947,275 filed on Nov. 29, 2007.

BACKGROUND

This invention relates to alpha-fluoroalkyl compounds related to tetrabenazine and dihydrotetrabenazine and intermediates useful in the preparation of such alpha-fluoroalkyl compounds.

Since first reported on in 1957 (Pletscher, A. (1957) Release of 5-hydroxytryptamine by benzoquinolizine derivatives with sedative action, Science 126, 507), tetrabenazine and structurally related compounds have been widely investigated, and a number of TBZ compounds and derivatives of tetrabenazine have shown promise in the treatment of a variety of conditions affecting human health. For example, dihydrotetrabenazine has been identified as an agent for the treatment of schizophrenia and other psychoses (See for example WO 2007017654 A1), and tetrabenazine has shown promise as an agent in the treatment of Huntington's disease (Neurology (2006), 66(3), 366-372). Although most preparations used in biological studies of tetrabenazine and its derivatives have been carried out on racemates, in at least one instance the biological activity exhibited by enantiomers tested separately was highly differentiated (See Koeppe, R. A. et al. (1999) Assessment of extrastriatal vesicular monoamine transporter binding site density using stereoisomers of [11C] dihydrotetrabenazine, J Cereb Blood Flow Metab 19, 1376-1384).

More recently, derivatives of 9-desmethyl(±)-dihydrotetrabenazine incorporating a fluorine-18 atom have been shown to be useful as PET imaging agents, Nuclear Medicine and Biology 33 (2006) 685-694. See also Nuclear Medicine and Biology 34 (2007) 239-246; and Nuclear Medicine and Biology 34 (2007) 233-237.

The present invention provides both a new class of fluorinated dihydrotetrabenazine derivatives and fluorinated dihydrotetrabenazine analogs, and discloses efficient synthetic methodology which may be used to prepare such compounds in enantiomerically enriched or racemic forms. The alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention are useful as PET imaging agents, probes for the development of PET imaging agents, and therapeutic agents. In addition, the present invention provides novel synthetic intermediate compositions which may be used to prepare either or both enantiomers of the subject dihydrotetrabenazine derivatives and dihydrotetrabenazine analogs.

BRIEF DESCRIPTION

In one embodiment, the present invention provides an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In another embodiment, the present invention provides a PET imaging agent comprising an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

DETAILED DESCRIPTION

In the following specification and the claims, which follow, reference will be made to a number of terms, which shall be defined to have the following meanings.

The singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.

“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

As used herein, the term “solvent” can refer to a single solvent or a mixture of solvents.

Approximating language, as used herein throughout the specification and claims, may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about”, is not to be limited to the precise value specified. In some instances, the approximating language may correspond to the precision of an instrument for measuring the value.

As used herein, the term “aromatic radical” refers to an array of atoms having a valence of at least one comprising at least one aromatic group. The array of atoms having a valence of at least one comprising at least one aromatic group may include heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed exclusively of carbon and hydrogen. As used herein, the term “aromatic radical” includes but is not limited to phenyl, pyridyl, furanyl, thienyl, naphthyl, phenylene, and biphenyl radicals. As noted, the aromatic radical contains at least one aromatic group. The aromatic group is invariably a cyclic structure having 4n+2 “delocalized” electrons where “n” is an integer equal to 1 or greater, as illustrated by phenyl groups (n=1), thienyl groups (n=1), furanyl groups (n=1), naphthyl groups (n=2), azulenyl groups (n=2), anthraceneyl groups (n=3) and the like. The aromatic radical may also include nonaromatic components. For example, a benzyl group is an aromatic radical which comprises a phenyl ring (the aromatic group) and a methylene group (the nonaromatic component). Similarly a tetrahydronaphthyl radical is an aromatic radical comprising an aromatic group (C₆H₃) fused to a nonaromatic component —(CH₂)₄—. For convenience, the term “aromatic radical” is defined herein to encompass a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloaromatic groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like. For example, the 4-methylphenyl radical is a C₇ aromatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 2-nitrophenyl group is a C₆ aromatic radical comprising a nitro group, the nitro group being a functional group. Aromatic radicals include halogenated aromatic radicals such as 4-trifluoromethylphenyl, hexafluoroisopropylidenebis(4-phen-1-yloxy) (i.e., —OPhC(CF₃)₂PhO—), 4-chloromethylphen-1-yl, 3-trifluorovinyl-2-thienyl, 3-trichloromethylphen-1-yl (i.e., 3-CCl₃Ph-), 4-(3-bromoprop-1-yl)phen-1-yl (i.e., 4-BrCH₂CH₂CH₂Ph-), and the like. Further examples of aromatic radicals include 4-allyloxyphen-1-oxy, 4-aminophen-1-yl (i.e., 4-H₂NPh-), 3-aminocarbonylphen-1-yl (i.e., NH₂COPh-), 4-benzoylphen-1-yl, dicyanomethylidenebis(4-phen-1-yloxy) (i.e., —OPhC(CN)₂PhO—), 3-methylphen-1-yl, methylenebis(4-phen-1-yloxy) (i.e., —OPhCH₂PhO—), 2-ethylphen-1-yl, phenylethenyl, 3-formyl-2-thienyl, 2-hexyl-5-furanyl, hexamethylene-1,6-bis(4-phen-1-yloxy) (i.e., —OPh(CH₂)₆PhO—), 4-hydroxymethylphen-1-yl (i.e., 4-HOCH₂Ph-), 4-mercaptomethylphen-1-yl (i.e., 4-HSCH₂Ph-), 4-methylthiophen-1-yl (i.e., 4-CH₃SPh-), 3-methoxyphen-1-yl, 2-methoxycarbonylphen-1-yloxy (e.g., methyl salicyl), 2-nitromethylphen-1-yl (i.e., 2-NO₂CH₂Ph), 3-trimethylsilylphen-1-yl, 4-t-butyldimethylsilylphenl-1-yl, 4-vinylphen-1-yl, vinylidenebis(phenyl), and the like. The term “a C₃-C₁₀ aromatic radical” includes aromatic radicals containing at least three but no more than 10 carbon atoms. The aromatic radical 1-imidazolyl (C₃H₂N₂—) represents a C₃ aromatic radical. The benzyl radical (C₇H₇—) represents a C₇ aromatic radical.

As used herein the term “cycloaliphatic radical” refers to a radical having a valence of at least one, and comprising an array of atoms which is cyclic but which is not aromatic. As defined herein a “cycloaliphatic radical” does not contain an aromatic group. A “cycloaliphatic radical” may comprise one or more noncyclic components. For example, a cyclohexylmethyl group (C₆H₁₁CH₂—) is a cycloaliphatic radical which comprises a cyclohexyl ring (the array of atoms which is cyclic but which is not aromatic) and a methylene group (the noncyclic component). The cycloaliphatic radical may include heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed exclusively of carbon and hydrogen. For convenience, the term “cycloaliphatic radical” is defined herein to encompass a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like. For example, the 4-methylcyclopent-1-yl radical is a C₆ cycloaliphatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 2-nitrocyclobut-1-yl radical is a C₄ cycloaliphatic radical comprising a nitro group, the nitro group being a functional group. A cycloaliphatic radical may comprise one or more halogen atoms which may be the same or different. Halogen atoms include, for example; fluorine, chlorine, bromine, and iodine. Cycloaliphatic radicals comprising one or more halogen atoms include 2-trifluoromethylcyclohex-1-yl, 4-bromodifluoromethylcyclooct-1-yl, 2-chlorodifluoromethylcyclohex-1-yl, hexafluoroisopropylidene-2,2-bis(cyclohex-4-yl) (i.e., —C₆H₁₀C(CF₃)₂C₆H₁₀—), 2-chloromethylcyclohex-1-yl, 3-difluoromethylenecyclohex-1-yl, 4-trichloromethylcyclohex-1-yloxy, 4-bromodichloromethylcyclohex-1-ylthio, 2-bromoethylcyclopent-1-yl, 2-bromopropylcyclohex-1-yloxy (e.g., CH₃CHBrCH₂C₆H₁₀O—), and the like. Further examples of cycloaliphatic radicals include 4-allyloxycyclohex-1-yl, 4-aminocyclohex-1-yl (i.e., H₂NC₆H₁₀—), 4-aminocarbonylcyclopent-1-yl (i.e., NH₂COC₅H₈—), 4-acetyloxycyclohex-1-yl, 2,2-dicyanoisopropylidenebis(cyclohex-4-yloxy) (i.e., —OC₆H₁₀C(CN)₂C₆H₁₀O—), 3-methylcyclohex-1-yl, methylenebis(cyclohex-4-yloxy) (i.e., —OC₆H₁₀CH₂C₆H₁₀O—), 1-ethylcyclobut-1-yl, cyclopropylethenyl, 3-formyl-2-terahydrofuranyl, 2-hexyl-5-tetrahydrofuranyl, hexamethylene-1,6-bis(cyclohex-4-yloxy) (i.e., —OC₆H₁₀(CH₂)₆C₆H₁₀O—), 4-hydroxymethylcyclohex-1-yl (i.e., 4-HOCH₂C₆H₁₀—), 4-mercaptomethylcyclohex-1-yl (i.e., 4-HSCH₂C₆H₁₀—), 4-methylthiocyclohex-1-yl (i.e., 4-CH₃SC₆H₁₀—), 4-methoxycyclohex-1-yl, 2-methoxycarbonylcyclohex-1-yloxy (2-CH₃OCOC₆H₁₀O—), 4-nitromethylcyclohex-1-yl (i.e., NO₂CH₂C₆H₁₀—), 3-trimethylsilylcyclohex-1-yl, 2-t-butyldimethylsilylcyclopent-1-yl, 4-trimethoxysilylethylcyclohex-1-yl (e.g., (CH₃O)₃SiCH₂CH₂C₆H₁₀—), 4-vinylcyclohexen-1-yl, vinylidenebis(cyclohexyl), and the like. The term “a C₃-C₁₀ cycloaliphatic radical” includes cycloaliphatic radicals containing at least three but no more than 10 carbon atoms. The cycloaliphatic radical 2-tetrahydrofuranyl (C₄H₇O—) represents a C₄ cycloaliphatic radical. The cyclohexylmethyl radical (C₆H₁₁CH₂—) represents a C₇ cycloaliphatic radical.

As used herein the term “aliphatic radical” refers to an organic radical having a valence of at least one consisting of a linear or branched array of atoms which is not cyclic. Aliphatic radicals are defined to comprise at least one carbon atom. The array of atoms comprising the aliphatic radical may include heteroatoms such as nitrogen, sulfur, silicon, selenium and oxygen or may be composed exclusively of carbon and hydrogen. For convenience, the term “aliphatic radical” is defined herein to encompass, as part of the “linear or branched array of atoms which is not cyclic” a wide range of functional groups such as alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, conjugated dienyl groups, alcohol groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example carboxylic acid derivatives such as esters and amides), amine groups, nitro groups, and the like. For example, the 4-methylpent-1-yl radical is a C₆ aliphatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 4-nitrobut-1-yl group is a C₄ aliphatic radical comprising a nitro group, the nitro group being a functional group. An aliphatic radical may be a haloalkyl group which comprises one or more halogen atoms which may be the same or different. Halogen atoms include, for example; fluorine, chlorine, bromine, and iodine. Aliphatic radicals comprising one or more halogen atoms include the alkyl halides trifluoromethyl, bromodifluoromethyl, chlorodifluoromethyl, hexafluoroisopropylidene, chloromethyl, difluorovinylidene, trichloromethyl, bromodichloromethyl, bromoethyl, 2-bromotrimethylene (e.g., —CH₂CHBrCH₂—), and the like. Further examples of aliphatic radicals include allyl, aminocarbonyl (i.e., —CONH₂), carbonyl, 2,2-dicyanoisopropylidene (i.e., —CH₂C(CN)₂CH₂—), methyl (i.e., —CH₃), methylene (i.e., —CH₂—), ethyl, ethylene, formyl (i.e., —CHO), hexyl, hexamethylene, hydroxymethyl (i.e., —CH₂OH), mercaptomethyl (i.e., —CH₂SH), methylthio (i.e., —SCH₃), methylthiomethyl (i.e., —CH₂SCH₃), methoxy, methoxycarbonyl (i.e., CH₃OCO—), nitromethyl (i.e., —CH₂NO₂), thiocarbonyl, trimethylsilyl (i.e., (CH₃)₃Si—), t-butyldimethylsilyl, 3-trimethyoxysilylpropyl (i.e., (CH₃O)₃SiCH₂CH₂CH₂—), vinyl, vinylidene, and the like. By way of further example, a C₁-C₁₀ aliphatic radical contains at least one but no more than 10 carbon atoms. A methyl group (i.e., CH₃—) is an example of a C₁ aliphatic radical. A decyl group (i.e., CH₃(CH₂)₉—) is an example of a C₁₀ aliphatic radical.

As noted, in one embodiment the present invention provides an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

The alpha-fluoroalkyl dihydrotetrabenazine compounds I provided by the present invention are believed to possess a high affinity for Type 2 Vesicular Monoamine Transporters (VMAT-2), a group of biomarkers which are believed to correlate with diabetes, Parkinson's disease, and other neurological disorders in human patients. The inventors' recent discovery that substitution by fluorine is tolerated with respect to VMAT-2 binding in closely related novel alpha-fluoroalkyl tetrabenazine and dihydrotetrabenazine compounds supports the proposition that the compounds of present invention may be used as positron emission tomography (PET) imaging agents in studies targeting the VMAT-2 biomarker.

Thus, in one embodiment, the present invention provides radiolabeled alpha-fluoroalkyl dihydrotetrabenazine compounds falling within the scope of generic structure I comprising a fluorine-18 atom. Fluorine-18 labeled alpha-fluoroalkyl dihydrotetrabenazine compounds I are suitable for use as imaging agents for positron emission tomography (PET) screening of human patients for pathological conditions related to diabetes. Positron emission tomography has become a medical imaging technique of critical importance to human health.

In an alternate embodiment, the present invention provides alpha-fluoroalkyl dihydrotetrabenazine compounds falling within the scope of either generic structure I and comprising a fluorine-19 atom, a stable isotope of fluorine. The alpha-fluoroalkyl compounds comprising a fluorine-19 atom are useful in binding studies which allow the identification of those alpha-fluoroalkyl compounds possessing optimal affinity for a target biomarker, for example VMAT-2. A substantial binding affinity of a given fluorine-19 containing alpha-fluoroalkyl tetrabenzine or dihydrotetrabenazine compound for a target biomarker such as VMAT-2 is a reliable predictor of utility in PET imaging of the corresponding fluorine-18 containing alpha-fluoroalkyl compound. Based on data disclosed herein, alpha-fluoroalkyl dihydrotetrabenazine compounds I are believed to possess substantial binding affinity for the biomarker VMAT-2.

Although throughout this disclosure there is considerable focus on human health, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention are expected to be useful in the study and treatment of a variety of human and animal diseases as imaging agents, as probes for the development of imaging agents, and as therapeutic agents.

As noted the present invention provides novel alpha-fluoroalkyl dihydrotetrabenazine compounds I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical

Alpha-fluoroalkyl dihydrotetrabenazine compounds having structure I are illustrated in Table 1 below.

TABLE 1 Examples of Alpha-Fluoroalkyl Dihydrotetrabenazines Having Structure I Ring Position (“RP”) Stereochemistry Entry R¹ R² R³ R⁴ RP-2 RP-3 RP-12 1a

CH₃ CH₃ Ac R/S R/S R/S 1b

CH₃ CH₃ Ac R R R 1c

CH₃O CH₃O EtCO R/S R/S R/S 1d

CH₃O CH₃O H₂NCO R/S* R R 1e

EtO CH₃O H₂NCO R/S* S S 1f

EtO EtO H₂NCO S S S 1g

CH₃CH₂ CH₃CH₂ BnHNCO R/S R/S R/S 1h

CH₃O CH₃O MeNHCO R R R 1i

CH₃O CH₂CH₃ iPrCO R/S R/S R/S 1j

CH₃O H TMS** R/S R/S R *Diastereomeric mixture with ring position-2 being epimeric. **Trimethylsilyl

Structure I represents a genus of alpha-fluoroalkyl dihydrotetrabenazine compounds which includes the racemic compound 1a (Table 1) having both the R configuration and S configuration at ring positions-2, 3 and 12. In another embodiment, structure I represents alpha-fluoroalkyl dihydrotetrabenazine compound 1b (Table 1) having the R configuration (absolute stereochemistry) at ring positions-2, 3 and 12. In yet another embodiment, structure I represents compound 1f (Table 1) having absolute stereochemistry opposite that of compound 1b. Those having ordinary skill in the art will appreciate that the individual alpha-fluoroalkyl dihydrotetrabenazine compounds shown in Table 1 herein are illustrative of dihydrotetrabenazine (DTBZ) derivatives falling within the scope of generic structure I. Those skilled in the art will appreciate as well that alpha-fluoroalkyl dihydrotetrabenazine compounds 1d and 1e represent diastereomeric mixtures.

As noted, in one embodiment, the present invention provides an alpha-fluoroalkyl dihydrotetrabenzine compound having structure I which may be a racemic mixture (e.g. compound 1a (Table 1), a single enantiomer (e.g. compound 1b (Table 1), or a composition enantiomerically enriched in a single principal component enantiomer. Entries 2a-2c in Table 2 below illustrate alpha-fluoroalkyl dihydrotetrabenazine compounds I comprising a principal component enantiomer and at least one minor component enantiomer.

TABLE 2 Alpha-fluoroalkyl Dihydrotetrabenazine Compounds I Comprising A Principal Component Enantiomer And At Least One Minor Component Enantiomer. Structure of Principal Component Structure of Minor Component Entry Enantiomer Enantiomer 2a

2b

2c

In Table 2 the alpha-fluoroalkyl dihydrotetrabenazine compositions comprise a principal component enantiomer and a minor component enantiomer. In the alpha-fluoroalkyl dihydrotetrabenazine compositions illustrated in Table 2 the mole percentage of the principal component enantiomer is given as “mole %” and refers to the mole percentage of the principal component enantiomer having the structure shown relative to the amounts of all other alpha-fluoroalkyl dihydrotetrabenazine components in the composition. For the purposes of this discussion an alpha-fluoroalkyl dihydrotetrabenazine is any compound falling within the scope of generic structure I. Entry 2a represents an alpha-fluoroalkyl dihydrotetrabenazine composition comprising 98 mole % of the R, R, R principal component enantiomer shown and a lesser amount of the S, S, S minor component enantiomer. Entry 2c represents an alpha-fluoroalkyl dihydrotetrabenazine composition comprising 88 mole percent of the S, S, S principal component enantiomer having the structure shown and a lesser amount of the R, R, R minor component enantiomer. Entry 2b represents a pair of diastereomers comprising the R, S, R-enantiomer shown as the principal component enantiomer, and a minor component S, S, S-enantiomer.

In one embodiment, the present invention provides an alpha-fluoroalkyl dihydrotetrabenazine compound represented by structure I which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position-12.

In another embodiment, the present invention provides an alpha-fluoroalkyl dihydrotetrabenazine compound represented by structure I which is enantiomerically enriched and is comprised of at least 95 mole percent (mole %) of an enantiomer having the R configuration at ring position-3.

In one embodiment, the present invention provides an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I in which the fluorinated aliphatic radical at ring position-3 (—R¹) has a syn-configuration relative to the hydrogen at ring position-12. The principal component enantiomers of Entries 2a-2c of Table 2 illustrate alpha-fluoroalkyl dihydrotetrabenazine compounds in which the fluorinated aliphatic moiety at ring position-3 (—R¹) has a syn-configuration relative to the hydrogen at ring position-12.

In one embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising a principal component enantiomer having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

Principal component enantiomers having structure II are illustrated in Table 3 below.

TABLE 3 Principal Component Enantiomers Having Structure II Entry Structure 3a

3b

3c

In one embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising at least 80 mole percent of an enantiomer having structure II, for example the composition comprising the compound of Entry 3a (Table 3) wherein the R, R, R enantiomer shown represents at least 80 mole percent relative to the amounts of all other alpha-fluoroalkyl dihydrotetrabenazine components in the composition.

In an alternate embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound which is comprised of at least 95 mole % of an enantiomer having structure II, for example an alpha-fluoroalkyl dihydrotetrabenazine composition comprising the compound of Entry 3b (Table 3) wherein the R, R, R enantiomer shown represents at least 95 mole percent relative to the amounts of all other alpha-fluoroalkyl dihydrotetrabenazine components in the composition.

In one embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising a principal component enantiomer having structure II wherein R¹ is a C₅-C₁₀ fluorinated aliphatic radical; and R² and R³ are methoxy groups and which are illustrated in Table 4 below.

TABLE 4 Principal Component Enantiomers Having Structure II Wherein R¹ Is A C₅-C₁₀ Fluorinated Aliphatic Radical And R² And R³ Are Methoxy Groups Entry Structure 4a

4b

4c

4d

In one embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising a principal component enantiomer having structure III

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

Principal component enantiomers having structure III are illustrated in Table 5 below.

TABLE 5 Principal Component Enantiomers Having Structure III Entry Structure 5a

5b

5c

In one embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising at least 80 mole percent of an enantiomer having structure III, for example an alpha-fluoroalkyl dihydrotetrabenazine composition comprising the compound of Entry 5a (Table 5) wherein the S, S, S enantiomer shown represents at least 80 mole percent relative to the amounts of all other alpha-fluoroalkyl dihydrotetrabenazine components in the composition. In another embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising at least 95 mole percent of an enantiomer having structure III, for example an alpha-fluoroalkyl dihydrotetrabenazine composition comprising the compound of Entry 5b (Table 5) wherein the S, S, S enantiomer shown represents at least 95 mole percent relative to the amounts of all other alpha-fluoroalkyl dihydrotetrabenazine components in the composition.

In another embodiment, the present invention provides an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising a principal component enantiomer having structure III wherein R¹ is a C₅-C₁₀ fluorinated aliphatic radical; and R² and R³ are methoxy groups, and which are illustrated in Table 6 below.

TABLE 6 Principal Component Enantiomers Having Structure III Wherein R¹ Is A C₅-C₁₀ Fluorinated Aliphatic Radical; And R² And R³ Are Methoxy Groups Entry Structure 6a

6b

6c

6d

The alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention are at times herein referred to collectively as “alpha-fluoroalkyl compounds” and comprise a derivitized OH group at ring position-3. As will be clear to one of ordinary skill in the art, the term “alpha-fluoroalkyl” refers to the group R¹ of structures I-III which represents a C₁-C₁₀ aliphatic radical and is not restricted to the ordinary meaning of the term “alkyl”. Thus although the term alpha-fluoroalkyl dihydrotetrabenazine is used extensively herein for convenience and means a dihydrotetrabenazine compound comprising a C₁-C₁₀ fluorinated aliphatic radical at ring position-3.

As noted, the alpha-fluoroalkyl dihydrotetrabenazine compounds I, II, and III provided by the present invention may comprise a fluorine-18 atom in the fluorinated aliphatic moiety —R¹. In various embodiments such alpha-fluoroalkyl compounds comprising a fluorine-18 atom are useful as PET imaging agents. Thus, in one embodiment, the present invention provides a PET imaging agent comprising an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical comprising at least one fluorine-18 atom; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising a principal component enantiomer having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical comprising at least one fluorine-18 atom; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In yet another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound comprising a principal component enantiomer having structure III

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical comprising at least one fluorine-18 atom; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.

In another embodiment, the present invention provides a PET imaging agent comprising an enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound having structure I, wherein R¹ is a C₅-C₁₀ fluoraliphatic radical comprising at least one fluorine-18 atom; and R² and R³ are methoxy groups.

The term “PET imaging agent” as used herein refers to a composition comprising a fluorine-18 labeled alpha-fluoroalkyl dihydrotetrabenazine compound which may be administered to a patient in order to perform a PET scan. Typically, the imaging agent is presented to the patient in the form of an aqueous formulation containing a sufficient amount of fluorine-18 labeled alpha-fluoroalkyl dihydrotetrabenazine compound to conduct the PET scan. Typically, the amount of fluorine-18 labeled alpha-fluoroalkyl dihydrotetrabenazine compound presented to a patient corresponds to a weight of the fluorine-18 labeled alpha-fluoroalkyl compound on the order of nanograms. In reference to the relative amounts of non-radioactive fluorine-19 containing alpha-fluoroalkyl compound present in the PET imaging agent presented to a patient, the PET imaging agent typically has a specific activity in a range from about 0.01 to about 10 percent. In one embodiment, the PET imaging agent has a specific activity in a range from about 0.01 to about 5 percent. In another embodiment, the PET imaging agent has a specific activity in a range from about 0.01 to about 1 percent.

The aqueous formulation containing the fluorine-18 alpha-fluoroalkyl dihydrotetrabenazine compound is typically administered intravenously and may contain various agents which promote the dispersal of the PET imaging agent in water. In one embodiment, the PET imagining agent may be administered to a patient in an aqueous formulation comprising ethanol and the fluorine-18 labeled alpha-fluoroalkyl compound. In an alternate embodiment, the PET imagining agent may be administered to a patient as an aqueous formulation comprising dextrose and the fluorine-18 labeled alpha-fluoroalkyl compound. In yet another embodiment, the PET imagining agent may be administered to a patient as an aqueous formulation comprising saline and the fluorine-18 labeled alpha-fluoroalkyl compound.

In addition to being useful as PET imaging agents and as probes for determining the suitability of a given alpha-fluoroalkyl compound for use as a PET imaging agent, the alpha-fluoroalkyl compounds provided by the present invention are believed to possess therapeutic utility in the treatment of diseases such as schizophrenia, Huntington's disease, and Parkinson's disease. Thus, in one embodiment, the present invention provides an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I which is useful in treating a pathological condition in a patient. In various other embodiments, the present invention provides enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compounds II and III, and mixtures thereof, which are useful in treating a pathological condition in a patient. Typically the amount of the alpha-fluoroalkyl compound administered to a patient in a given dose is on the order of milligrams.

Those skilled in the art will appreciate that alpha-fluoroalkyl compounds such as alpha-fluoroalkyl compounds falling within the scope of generic structure I may under a variety of conditions form salts which are useful as PET imaging agents, probes for the discovery and development of imaging agents, and/or therapeutic agents. Thus, the present invention provides a host of novel and useful alpha-fluoroalkyl compounds and their salts. For example, in one particular embodiment, the present invention provides the hydrochloride salts of the novel alpha-fluoroalkyl compounds, for example the hydrochloride salt of the compound of Entry 4a of Table 4.

The alpha-fluoroalkyl dihydrotetrabenazine compounds I of the present invention may be prepared by a variety of methods including those provided in the experimental section of this disclosure. In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compound I is prepared by reaction of nucleophilic fluoride ion or an electrophilic fluorinating agent with a fluorophilic tetrabenazine- or dihydrotetrabenazine compound having structure IV

wherein Q is a carbonyl group, a protected carbonyl group, a hydroxy methine group, or a protected hydroxy methine group; R¹ is a C₁-C₂₀ aliphatic, C₂-C₂₀ cycloaliphatic, or C₂-C₂₀ aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R² is hydrogen or a C₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphatic radical. Where Q is a carbonyl group, a protected carbonyl group, or a hydroxy methine group, access to the alpha-fluoroalkyl dihydrotetrabenazine compounds of the present invention may involve additional chemical transformation (e.g. acetylation) following reaction of compound IV with nucleophilic fluoride ion or an electrophilic fluorinating agent.

Fluorophilic tetrabenazine- and dihydrotetrabenazine compounds having structure IV are illustrated in Table 7 below.

TABLE 7 Examples of Fluorophilic Tetrabenazine- and Dihydrotetrabenazine Compounds Having Structure IV Ring Position (“RP”) Stereochemistry Entry R¹ R² R³ Q RP-2 RP-3 RP-12 7a

CH₃ CH₃

R/S R/S R/S 7b

CH₃ CH₃

R R R 7c

CH₃O CH₃O

— R/S R/S 7d

CH₃O CH₃O

R R R 7e

EtO CH₃O

— S S 7f

EtO EtO

S S S 7g

CH₃CH₂ CH₃CH₂

R/S R/S R/S 7h

CH₃O CH₃O

R R R 7i CH₃O CH₂CH₃

R/S R/S R/S 7j

CH₃O H

R/S R/S R 7k

CH₃O CH₃O

R R R 7l

CH₃O CH₃O

— S S

As provided for in generic structure IV, the fluorophilic tetrabenazine- and dihydrotetrabenazine compounds which may be used to prepare the compounds of the present invention include compounds which are formally tetrabenazine compounds (i.e., Q is a carbonyl group, for example Entries 7c and 7e of Table 7); compounds which are dihydrotetrabenazine compounds bearing a free hydroxy group at ring (i.e., Q is a hydroxy methine group, for example Entry 7b of Table 7); “protected” tetrabenazine compounds (i.e., Q is a protected carbonyl group, for example Q is ethylene ketal group as found in tetrabenazine ketal tosylate 33 of Example 4 herein); or dihydrotetrabenazine compounds not bearing a free hydroxy group at ring position-2 (i.e., Q is a “protected” hydroxy methine group, for example Q is a CHOTHP group as in Entry 7a of Table 7 and in tosylate 34 of Example 5 herein). The term “protected carbonyl group” refers to a carbonyl group equivalent, usually a carbonyl group which has been transformed into a functional group such as a ketal, thioketal, or dithioketal group; and the term “protected hydroxy methine group” refers to a hydroxy methine group equivalent, usually a hydroxy methine group which has been transformed into a functional group such as a tetrahydropyranyl (THP) ether group, a methoxymethyl ether group (MOM group), a methoxyethoxyether group (MEM group), a methylthiomethyl ether group, a benzyl ether group, a p-methoxybenzyl ether group, a pivaloyl ester group (OPiv), or an actetyl ester group (OAc). Protection agents which may be used to transform a carbonyl group or a hydroxy methine group into a protected carbonyl group or a protected hydroxy methine group are well known in the art, for example protection agents detailed in Protecting Groups In Organic Synthesis by James R. Hanson (Blackwell Science, 1999) and Greene's Protective Groups in Organic Synthesis (Wiley-Interscience, 2006).

As noted, in one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV, wherein R¹ is a C₁-C₂₀ aliphatic radical, a C₂-C₂₀ cycloaliphatic radical, or a C₂-C₂₀ aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion. In one embodiment, the functional group susceptible to reaction with nucleophilic fluoride ion is an aromatic sulfonate ester (e.g. tosylate, benzenesulfonate, naphthalenesulfonate). In an alternate embodiment, the functional group susceptible to reaction with nucleophilic fluoride ion is an aliphatic sulfonate ester (e.g. methane sulfonate, trifluoromethane sulfonate). In one embodiment, the functional group susceptible to reaction with nucleophilic fluoride ion is selected from the group consisting of tosylate, mesylate, and trifluoromethane sulfonate groups.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV wherein the group R¹ comprises at least one tosylate group susceptible to reaction with nucleophilic fluoride ion. See for example the Entries 7a, 7j and 7k of Table 7. As defined herein, the tosylate group is an aromatic radical and the group R¹ comprising the tosylate group is also an aromatic radical. In the compound shown in Entry 7a for example, the group R¹ comprising the tosylate group is a C₉ aromatic radical which upon displacement with fluoride ion becomes a C₂ fluorinated aliphatic radical.

In an alternate embodiment, alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV wherein the group R¹ comprises at least one mesylate group (methane sulfonate group) susceptible to reaction with nucleophilic fluoride ion. As defined herein, the mesylate group is an aliphatic radical and the group R¹ comprising the mesylate group may be an aliphatic, a cycloaliphatic or an aromatic radical depending on the overall structure of the group R¹. For example, in a fluorophilic compound having structure IV in which R¹ comprises both a mesylate group and an epoxy group, the group R¹ may be a cycloaliphatic radical. Alternatively, in a fluorophilic compound having structure IV in which R¹ comprises both a mesylate group and a tosylate group, the group R¹ is an aromatic radical. It is helpful to bear in mind that the definitions of aliphatic, cycloaliphatic and aromatic radicals provided in this disclosure establish a hierarchy in which aliphatic radicals (non-cyclic arrays of atom(s)) must be free of cycloaliphatic groups (a cyclic array of atoms which is not aromatic) and aromatic groups (a cyclic array of atoms which is aromatic), cycloaliphatic radicals must be free of aromatic groups, and aromatic radicals must simply comprise an aromatic group.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV wherein the group R¹ comprises at least one trifluoromethane sulfonate (triflate) group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 7b of Table 7.

In an alternate embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV wherein the group R¹ comprises at least one p-nitrobenzoate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 7c of Table 7.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV wherein the group R¹ comprises at least one epoxy group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 7i of Table 7.

In yet another embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV wherein the group R¹ comprises at least one cyclic sulfate group susceptible to reaction with nucleophilic fluoride ion. See for example Entry 71 of Table 7.

In one embodiment, the alpha-fluoroalkyl dihydrotetrabenazine compounds provided by the present invention may be prepared from a fluorophilic compound having structure IV, wherein R¹ is a C₂-C₂₀ aliphatic radical comprising at least one functional group susceptible to reaction with an electrophilic fluorinating agent, for example fluorine gas, perchloryl fluoride, mercuric fluoride, and phenyl selenenyl fluoride.

Thus in one embodiment, the functional group susceptible to reaction with an electrophilic fluorinating agent is selected from the group consisting of carbon-carbon double bonds and carbon-carbon triple bonds. Entries 7e, 7f, 7g, 7h and 7k of Table 7 illustrate compounds falling within the scope of generic structure IV which are susceptible to reaction with an electrophilic fluorinating agent. Attention is called to Entry 7k wherein the group R¹ comprises functional groups susceptible to reaction with an electrophilic fluorinating agent (double bond) and to reaction with nucleophilic fluoride ion (tosylate group). Entry 7k of Table 7 also features a thioketal carbonyl protecting group. As used herein a thioketal protecting group comprises both an oxygen and a sulfur atom bonded to the “carbonyl carbon” and is distinguished from a dithioketal which comprises two sulfur atoms attached to the “carbonyl carbon”.

Fluorophilic tetrabenazine- and dihydrotetrabenazine compounds IV may be prepared in enantiomerically enriched or racemic forms. For example, a fluorophilic dihydrotetrabenazine compound IV may be enriched in the R,R,R-enantiomer shown in Entry 7h (a fluorophilic dihydrotetrabenazine compound) of Table 7. Alternatively, a fluorophilic tetrabenazine- or dihydrotetrabenazine compound IV may be enriched in an enantiomer having absolute stereochemistry opposite that of Entry 7d of Table 7, for example the S,S,S-enantiomer of Entry 7f.

Thus, in one embodiment, the compounds of the present invention may be prepared from an enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having structure V

wherein Q is a carbonyl group, a protected carbonyl group, a hydroxy methine group, or a protected hydroxy methine group; R¹ is a C₁-C₂₀ aliphatic, C₂-C₂₀ cycloaliphatic, or C₂-C₂₀ aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R² is hydrogen or a C₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphatic radical. Principal component enantiomers V are illustrated by Entries 7b, 7d, 7h, and 7k of Table 7. Where Q is a carbonyl group, a protected carbonyl group, or a hydroxy methine group, access to the alpha-fluoroalkyl dihydrotetrabenazine compounds of the present invention may involve additional chemical transformation (e.g. acetylation) following reaction of compound V with nucleophilic fluoride ion or an electrophilic fluorinating agent.

In an alternate embodiment, the compounds of the present invention may be prepared from an enantiomerically enriched fluorophilic compound comprising a principal component enantiomer having structure VI

wherein Q is a carbonyl group, a protected carbonyl group, a hydroxy methine group, or a protected hydroxy methine group; R¹ is a C₁-C₂₀ aliphatic, C₂-C₂₀ cycloaliphatic, or C₂-C₂₀ aromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; R² is hydrogen or a C₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphatic radical. Principal component enantiomers VI are illustrated by Entries 7e and 7f of Table 7. Where Q is a carbonyl group, a protected carbonyl group, or a hydroxy methine group, access to the alpha-fluoroalkyl dihydrotetrabenazine compounds of the present invention may involve additional chemical transformation (e.g. acetylation) following reaction of compound VI with nucleophilic fluoride ion or an electrophilic fluorinating agent.

Co-pending U.S. patent application Ser. No. 11/760,359 and Ser. No. 11/760,372 filed Jun. 8, 2007 disclose methods for the preparation of racemic and enantiomerically enriched tetrabenazine- and dihydrotetrabenazine compositions IV which may be used in the preparation of compounds of the present invention. In addition, the Examples Section of the present disclosure provides detailed experimental descriptions of the preparation and characterization of fluorophilic tetrabenazine- and dihydrotetrabenazine compounds IV and their conversion to alpha-fluoroalkyl dihydrotetrabenazine compounds I.

In general, fluorophilic tetrabenazine and dihydrotetrabenazine compounds IV can be prepared by reacting a nucleophilic alkenyl species with an aldehyde compound having structure VII

wherein R² is hydrogen or a C₁-C₁₀ aliphatic radical; and R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and P¹ is a protecting group, to provide an allylic alcohol (See Methods 4, 5, and 6 of the Examples section), which is then oxidized to provide an enone designated the “first intermediate” (See Methods 7, 8, and 9 of the Examples section), the protecting group P¹ of which is then removed and the resultant deprotected first intermediate undergoes an amino cyclization reaction to afford the corresponding tetrabenazine compound.

Representative aldehyde compounds encompassed by generic formula VII are given in Table 8.

TABLE 8 Representative Aldehyde Compounds Encompassed By Formula VII Ring Position* Compound Stereo- Entry Type chemistry Structure 8a Single “R” enantiomer, “Boc” protecting group P¹ RP-12 “R”

8b Single “S” enantiomer, “Boc” protecting group P¹ RP-12 “S”

8c Enantiomeric ally enriched mixture of “R” and “S” enantiomers, “alloc” protecting group P¹ RP-12 “R/S”

8d Racemic mixture of “R” and “S” enantiomers; “Fmoc” protecting group P¹ RP-12 “R/S”

8e Racemic mixture of “R” and “S” enantiomers; “Cbz” protecting group P¹ RP-12 “R/S”

8f Racemic mixture of “R” and “S” enantiomers; “Teoc” protecting group P¹ RP-12 “R/S”

8g Single “R” enantiomer, “Boc” protecting group P¹ RP-12 “R”

The preparation of the aldehyde compound featured in Entry 8a of Table 8 is described in the Examples section of this disclosure (Methods 1-3). In general, the class of aldehyde compounds represented by structure VII may be prepared by art recognized methods, for example using the methodology depicted in Scheme 1. Those skilled in the art will appreciate that as depicted in Scheme 1 the protecting group P¹ represents a “Boc” protecting group.

Thus, aldehyde compounds VII may be prepared from intermediates prepared using methodology described by Sasamoto et al. (Journal of the American Chemical Society 128, 14010-14011, 2006). Sasamoto et al. disclose the preparation of enantiomerically enriched tetrahydroquinoline malonate compounds which may be converted as shown in the present disclosure to aldehyde compound VII by selective hydrolysis of one of the ester moieties of the tetrahydroquinoline malonate and decarboxylation followed by reduction of the resultant tetrahydroisoquinoline monoester to aldehyde compound VII as depicted in Scheme 1.

One of ordinary skill in the art will appreciate that the 2 mole percent DM-SEGPHOS shown in Scheme 1 represents a chiral catalyst responsible for the enantiomeric enrichment of the product aldehyde VII, and further that the use of DM-SEGPHOS of opposite chirality as the chiral catalyst will afford a product aldehyde VII enantiomerically enriched in the “S” enantiomer (aldehyde compound VII having the S configuration at ring position-12 (See for example Entry 8b of Table 8). Suitable chiral catalysts include those disclosed by Sasamoto et al. (Journal of the American Chemical Society 128, 14010-14011, 2006), for example (S)-Binap, (R)-Binap, (S)-DM-Binap, (R)-DM-Binap, (S)-DM-SEGPHOS, and (R)-DM-SEGPHOS. Typically use of a catalyst consisting of a ligand possessing a single, for example “S”, configuration produces stereochemically enriched malonate adducts of the opposite “R” configuration and vice versa.

In addition to the use of a chiral catalyst to generate aldehyde compounds VII enriched in a single configuration at ring position-12, there are available a wide variety of methods for the separation of racemic aldehyde VII into its constituent enantiomers. For example, racemic aldehyde compound VII may be separated into its constituent enantiomers by high performance liquid chromatography (hplc) on a chiral hplc column.

Other methods for producing enantiomerically enriched compositions provided by the present invention include conversion of a racemic alpha-fluoroalkyl compound having structure I compound into an adduct comprising a mixture of diastereomers which are then separated by fractional crystallization. For example, a racemic alpha-fluoroalkyl compound having structure I may be reacted with (−)-tartaric acid to form an adduct (ammonium tartarate salt) of the racemic alpha-fluoroalkyl compound, said adduct comprising a mixture of diastereomeric ammonium tartarate salts which are then separated by fractional crystallization.

METHODS AND EXAMPLES

The following Examples and Methods are intended only to illustrate methods and embodiments in accordance with the invention, and as such should not be construed as imposing limitations upon the claims.

Method 1 Preparation of Protected Diester 2

The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH₂Cl₂ at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0° C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at ˜2.5° C. for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO₂ (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α]²⁶ _(D) −69.0 (c 0.21, CHCl₃); ¹H NMR (CDCl₃) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz, 0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s, 0.6H), 6.81 (s, 0.4H); ¹³C NMR (CDCl₃) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06.

Method 2 Selective Hydrolysis and Decarboxylation of Protected Diester 2

The starting material 2 was taken up in isopropanol to provide a 0.2 M solution of 2. To this solution was added 1M aqueous NaOH solution bringing the final concentration of the reaction mixture to 0.1M with respect to the malonate 2. The reaction mixture was heated to and maintained 70° C. for 22 min. (timing was started when the temperature of the reaction mixture temp exceeded 65° C.). Following the allotted time the reaction mixture was quickly cooled to 0° C. The reaction mixture carefully acidified with 2M aqueous HCl and extracted with three portions of dichloromethane. The combined organic extracts dried (Na₂SO₄), filtered and concentrated under reduced pressure. The isolated material was taken up in THF to provide a 0.1 M solution (based on the original quantity of 2 used in the reaction mixture) and triethylamine (1.0 eq) was added to the reaction mixture at room temperature. The reaction mixture was heated to its reflux temperature and maintained at this temperature for 90 min. The reaction mixture was concentrated under reduced pressure, dissolved in a minimal quantity of CH₂Cl₂ and was immediately purified by column chromatography on SiO₂ (15-40% EtOAc-hexanes; 40%, the eluant was monitored at 284 nm). The product 3 existed as a mixture of rotamers at room temperature and was a colorless foam 79%: [α]²⁶ _(D) −82 (c 0.24, CH₂Cl₂); ¹H NMR (CDCl₃) δ 1.19-1.25 (m, 6H), 1.43-1.49 (m, 9H), 2.58-2.69 (m, 2H), 2.70-2.77 (m, 1H), 2.78-2.92 (m, 1H), 3.13-3.43 (m, 1H), 3.81-3.85 (m, 6H), 3.86-4.01 (m, 1H), 4.91-5.05 (m, 1H), 5.38-5.61 (m, 1H), 6.56-6.61 (m, 1H), 6.64-6.70 (s, 1H); ¹³C NMR (CDCl₃) δ 21.75, 21.90, 27.93, 28.08, 28.44, 37.53, 38.75, 42.22, 42.81, 51.11, 51.87, 55.92, 56.02, 68.08, 79.74, 80.21, 109.60, 109.99, 111.44, 111.54, 126.28, 126.48, 128.54, 128.76, 147.51, 147.97, 154.39, 154.51, 170.36, 170.59; LRMS-(ESI+) calcd for (C₂₁H₃₁NO₆+H) [M+H]⁺ 394.22, found 394.16.

Method 3 Preparation of Aldehyde Compound 4

To a 0.12 M solution of the starting monoester (3, 1.0 eq.) in toluene at −78° C. was added a 1.5 M solution of DiBAl—H in hexanes (1.5 eq.) dropwise via a syringe pump. Following the addition the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched by the addition of EtOAc and was then acidified with saturated aqueous citric acid solution. The reaction mixture was allowed to warm to room temperature and continue stirring for 30 min. The phases were separated, and the aqueous layer extracted with three portions of EtOAc. The combined organic extracts were washed with two portions of 2 M aqueous HCl solution, brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude product was subjected purification on SiO₂ (15-35% EtOAc-hexanes; Elution was observed at 285 nm and 228 nm). The isolated product aldehyde compound 4 was a colorless foam. The product existed as a 1:1 mixture of rotamers at room temperature 76%: [α]²⁶ _(D) −116 (c 0.26, CH₂Cl₂); ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 2.58 (apparent t, J=3.8 Hz, 0.5H), 2.61 (apparent t, J=3.5 Hz, 0.5H), 2.68-2.88 (m, 3H), 3.02-3.27 (m, 1H), 3.78 (apparent s, 6H), 3.87-3.99 (m, 0.5H), 4.08-4.23 (m, 0.5H), 5.37-5.68 (m, 1H), 6.55 (s, 1H), 6.58 (s, 1H), 9.78 (s, 1H); ¹³C NMR (CDCl₃) δ 20.90, 28.02, 28.27, 37.23, 38.65, 49.29, 49.93, 51.12, 55.83, 55.96, 80.13, 80.64, 109.42, 109.52, 111.52, 126.34, 126.51, 127.78, 127.82, 147.72, 147.97, 153.85, 154.62, 200.08, 200.33.

Method 4 Reaction of Aldehyde Compound 4 with Nucleophilic Alkenyl Species Derived from Alkenyl Iodide 5 with to Provide Allylic Alcohol 6

To a neat mixture of the alkenyl iodide 5 (1.0 eq) and the aldehyde compound 4 (1.0 eq.) at room temperature was added 2.65 eq. of chromium chloride doped with 0.5% NiCl₂ (w/w). The mixture was vortexed for about 2 min. to provide a homogeneous, green/grey paste and then stirred under nitrogen for an additional 10 min. after which time anhydrous DMF was added to bring the final reaction concentration to 0.36 M. The reaction mixture was deep green in color and was permitted to continue stirring at room temperature for 14 h. Following the allotted time, the reaction mixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTA solution (pH 9) was added and the entire mixture was allowed to stir for 1.5 h. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO₄), filtered, and the filtrate was concentrated under reduced pressure to provide a green oil. The crude material was subjected to column chromatography on SiO₂ (35% EtOAc-hexanes; elution was observed at 285 nm and 228 nm). The product allylic alcohol 6 was a pale yellow oil isolated in 53% yield as a mixture of diastereomers which was taken on to the next step without additional characterization or analysis.

Method 5 Reaction of Aldehyde Compound 4 with Nucleophilic Alkenyl Species Derived from Alkenyl Iodide 7 with to Provide Allylic Alcohol 8

To a neat mixture of the alkenyl iodide 7 (1.0 eq) and the aldehyde compound 4 (1.25 eq.) at room temperature was added 2.5 eq. of chromium chloride doped with 0.5% NiCl₂ (w/w). The mixture was vortexed for about 2 min. to provide a homogeneous, green/grey paste and then stirred under nitrogen for an additional 10 min. after which time anhydrous DMF was added to bring the final reaction concentration to 0.32 M. The reaction mixture was deep green in color and was permitted to continue stirring at room temperature for 14 h. Following the allotted time, the reaction mixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTA solution (pH 9) was added and the entire mixture was allowed to stir for 1.5 h. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO₄), filtered, and the filtrate was concentrated under reduced pressure to provide a green oil. The crude material was subjected to column chromatography on SiO₂ (20% EtOAc-hexanes to 35% EtOAc-hexanes; elution was observed at 285 nm and 228 nm). The product allylic alcohol 8 was a pale yellow oil isolated in 54% yield as a mixture of diastereomers which was taken on to the next step without additional characterization or analysis.

Method 6 Reaction of Aldehyde Compound 4 with Nucleophilic Alkenyl Species Derived from Alkenyl Iodide 9 with to Provide Allylic Alcohol 10

To a neat mixture of the alkenyl iodide 9 (1.5 eq) and the aldehyde 4 (1.0 eq.) at room temperature was added 2.5 eq. of chromium chloride doped with 0.5% NiCl₂ (w/w). The mixture was vortexed for about 2 min. to provide a homogeneous, green/grey paste and then stirred under nitrogen for an additional 10 min. after which time anhydrous DMF was added to bring the final reaction concentration to 0.36 M. The reaction mixture was deep green in color and was permitted to continue stirring at room temperature for 14 h. Following the allotted time, the reaction mixture was diluted with 1:1 EtOAc-hexanes and an aqueous 0.5 M EDTA solution (pH 9) was added and the entire mixture was allowed to stir for 1.5 h. The aqueous layer was extracted with three portions of EtOAc, dried (MgSO₄), filtered, and the filtrate was concentrated under reduced pressure to provide a green oil. The crude material was subjected to column chromatography on SiO₂ (40% EtOAc-hexanes; elution was observed at 285 nm and 228 nm) to afford the product allylic alcohol 10 as a pale yellow oil that existed as a 1:1 mixture of diastereomers (47%): ¹H NMR (CD₂Cl₂) δ 0.94-1.00 (m, 6H), 1.13-1.16 (m, 9H), 1.54-1.57 (m, 9H), 1.67-1.74 (m, 2H), 1.79-1.86 (m, 0.5H), 1.87-1.94 (m, 1H), 1.96-2.05 (m, 0.5H), 2.09-2.24 (m, 2H), 2.66-2.77 (m, 1H), 2.85-2.99 (m, 1H), 3.16-3.22 (m, 0.5H), 3.36-3.44 (m, 0.5H), 3.80-3.92 (m, 8H), 4.01-4.08 (m, 0.5H), 4.12-4.17 (m, 0.5H), 4.30-4.38 (m, 0.5H), 4.66-4.77 (m, 0.5H), 4.86-4.96 (m, 1H), 5.23-5.30 (m, 0.5H), 5.34-5.39 (m, 1H), 5.39-5.43 (m, 0.5H), 6.68-6.72 (m, 1H), 6.73-6.77 (m, 0.5H), 6.77-6.81 (m, 0.5H), 7.43-7.52 (m, 6H), 7.75-7.82 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.12, 26.83, 27.33, 27.45, 27.54, 27.59, 28.29, 28.41, 33.46, 33.48, 38.30, 39.45, 43.64, 43.82, 44.93, 45.05, 45.48, 45.95, 50.95, 52.25, 55.89, 55.99, 56.01, 61.14, 69.99, 73.06, 80.03, 80.49, 110.21, 110.56, 111.87, 112.00, 112.02, 112.39, 125.92, 126.32, 126.35, 127.77, 129.57, 129.69, 130.17, 134.15, 135.68, 147.85, 147.88, 147.99, 148.11, 148.71, 149.59, 149.61, 155.79, 156.39.

Method 7 Oxidation of Allylic Alcohol 6 to Provide First Intermediate 12

To a 0.1 M solution of allylic alcohol 6 (1.0 eq) in dichloromethane at 0° C. was added 1.1 eq. of the Dess-Martin reagent 11. The reaction mixture was allowed to stir, slowly warming to room temperature over 2.5 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and diluted with ethyl acetate. The organic and aqueous layers were partitioned and separated and the aqueous layer extracted with three additional portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO₂ (10-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product first intermediate 12 was a colorless, foul-smelling oil that existed at 26° C. as a 60:40 mixture of rotamers in solution (66%): ¹H NMR (CDCl₃) δ 0.82 (apparent t, J=7.6 Hz, 6H), 1.42 (s, 9H), 1.70 (apparent sept, J=6.62 Hz, 1H), 2.08-2.15 (m, 1H), 2.15-2.24 (m, 1H), 2.62-2.70 (m, 1H), 2.75-2.91 (m, 1H), 2.93-3.07 (m, 1H), 3.07-3.29 (m, 1.6H), 3.30-3.43 (m, 0.4H), 3.79 (s, 3H), 3.81 (s, 3.4H), 4.04-4.16 (m, 0.6H), 5.52-5.62 (m, 1H), 5.69 (s, 1H), 5.90 (s, 0.6H), 6.04 (s, 0.4H), 6.57 (s, 1H), 6.63 (s, 1H); ¹³C NMR (CDCl₃) δ 22.45, 27.04, 27.25, 28.11, 28.41, 38.01, 39.33, 40.39, 45.20, 45.90, 51.62, 55.92, 55.98, 79.75, 80.23, 109.85, 110.25, 110.28, 111.41, 125.65, 125.72, 126.26, 129.25, 147.57, 147.87, 148.16, 148.29, 148.35, 154.40, 154.51, 199.53; HRMS-(ESI+) calcd for (C₂₄H₃₅NO₅)+H) [M+H]⁺ 418.2594, found 418.2590.

Method 8 Oxidation of Allylic Alcohol 8 to Provide First Intermediate 13

To a 0.1 M solution of 8 (1.0 eq) in dichloromethane at 0° C. was added 1.1 eq. of the Dess-Martin reagent 11. The reaction mixture was allowed to stir, slowly warming to room temperature over 2.5 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and diluted with dichloromethane. The organic and aqueous layers were partitioned and separated and the aqueous layer extracted with three additional portions of dichloromethane. The combined organic extracts were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO₂ (10-50% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product first intermediate 13 was a colorless, oil that existed at 26° C. as a 50:50 mixture of rotamers in solution (82%): ¹H NMR (CD₂Cl₂) δ 1.19 (s, 9H), 1.55 (s, 9H), 1.63-1.83 (m, 5H), 2.34-2.57 (m, 2H), 2.70-2.85 (m, 1H), 2.85-3.05 (m, 1H), 3.05-3.41 (m, 2.5H), 3.41-3.56 (m, 0.5H), 3.81-3.83 (m, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 3.97-4.08 (m, 0.5H), 4.20-4.35 (m, 0.5H), 5.68 (apparent t, J=6.6 Hz, 1H), 5.87 (s, 1H), 6.09 (s, 0.5H), 6.19 (s, 0.5H), 6.71 (s, 1H), 6.76 (s, 1H), 7.45-7.60 (m, 6H), 7.77-7.95 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.19, 24.66, 24.75, 26.83, 28.06, 28.28, 30.57, 32.43, 37.75, 39.20, 45.16, 45.66, 63.84, 79.46, 79.77, 110.21, 110.49, 111.81, 124.37, 124.67, 126.45, 127.76, 129.19, 129.68, 134.13, 135.61, 147.79, 148.19, 149.20, 154.09, 154.41, 199.15, 199.27; HRMS-(ESI+) calcd for (C₄₀H₅₃NO₆Si+H) [M+H]⁺ 672.3720, found 672.3715.

Method 9 Oxidation of Allylic Alcohol 10 to Provide First Intermediate 14

To a 0.1 M solution of allylic alcohol 10 (1.0 eq) in dichloromethane at 0° C. was added 1.1 eq. of the Dess-Martin reagent 11. The reaction mixture was allowed to stir, slowly warming to room temperature over 5 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and diluted with dichloromethane. The organic and aqueous layers were partitioned and separated and the aqueous layer extracted with three additional portions of dichloromethane. The combined organic extracts were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on SiO₂ (10-50% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product first intermediate 14 was a yellow foam that existed at 26° C. as a 50:50 mixture of rotamers in solution (93%): ¹H NMR (CD₂Cl₂) δ 0.85 (s, 6H), 1.14 (s, 9H), 1.48-1.57 (m, 9H), 1.65 (t, J=7.3 Hz, 2H), 2.30-2.50 (m, 2H), 2.70-2.80 (m, 1H), 2.85-2.98 (m, 1H), 3.07-3.17 (m, 1H), 3.22-3.37 (m, 1.5H), 3.38-3.50 (m, 0.5H), 3.81 (s, 3H), 3.85 (s, 3H), 3.85-3.92 (m, 2H), 3.94-4.02 (m, 0.5H), 4.18-4.25 (m, 0.5H), 5.65-5.72 (m, 1H), 5.74 (s, 1H), 6.07 (s, 0.5H), 6.14 (s, 0.5H), 6.69 (s, 1H), 6.76 (s, 1H), 7.45-7.54 (m, 6H), 7.77-7.82 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.09, 26.80, 26.92, 26.97, 28.13, 28.22, 28.28, 33.22, 37.94, 39.39, 41.79, 41.87, 44.49, 45.33, 46.02, 51.16, 51.44, 55.79, 55.83, 61.05, 79.47, 79.76, 110.18, 110.51, 111.74, 126.40, 127.26, 127.36, 127.76, 129.48, 129.69, 134.09, 135.66, 146.93, 147.06, 147.78, 148.10, 154.16, 154.47, 199.36; HRMS-(ESI+) calcd for (C₄₂H₅₇NO₆Si—C₅H₉O₂(Boc)+H) [M-Boc+H]⁺ 600.3509, found 600.3496.

Method 10 Removal the Boc Protecting Group from First Intermediate 12 and Amino Cyclization Provide (+)-Tetrabenazine 15

First intermediate 12 (1.0 eq) was dissolved in 10% Me₂S-dichloromethane to provide an 82 mM solution. The solution was cooled to 0° C. and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0° C.) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0° C. for 1 h. Following the allotted time the reaction mixture was quenched at 0° C. by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)-tetrabenazine (15) 46%: mp 126.0° C. (3.5% DME-hexanes) (a crystal polymorph was observed at 116° C.); [α]²⁶ _(D)+37.2 (c 0.41, CH₂Cl₂); ¹H NMR (CD₂Cl₂) δ 0.89 (apparent t, J=7.2 Hz, 6H), 0.98 (ddd, J=12, 6.0, 4.0 Hz, 1H), 1.59-1.68 (m, 1H), 1.74 (ddd, J=12, 5.9, 5.7 Hz, 1H), 2.32 (apparent t, J=11.7 Hz, 1H), 2.46 (apparent t, J=12.3 Hz, 1H), 2.55 (ddd, J=12, 10.0, 3.8 Hz, 1H), 2.65-2.73 (m, 2H), 2.83 (dd, J=5.5, 2.8 Hz, 1H), 2.97-3.07 (m, 1H), 3.07-3.14 (m, 1H), 3.25 (dd, J=9.7, 6.3 Hz, 1H), 3.47 (apparent d, J=12 Hz, 1H), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, 1H), 6.60 (s, 1H) ¹³C NMR (CD₂Cl₂) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72; HRMS-(ESI+) calcd for (C₁₉H₂₇NO₃+H) [M+H]⁺ 318.2069, found 318.2082.

Method 11 Removal the Boc Protecting Group from First Intermediate 13 and Amino Cyclization Provide (+)-TBZ Compound 16

The first intermediate starting material 13 (1.0 eq) was dissolved in 10% Me₂S-dichloromethane to provide an 26 mM solution. The solution was cooled to 0° C. and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0° C.) was added to the reaction mixture to provide a final concentration of 13 mM. The reaction mixture was permitted to stir at 0° C. for 1 h. Following the allotted time the reaction mixture was quenched at 0° C. by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide an orange oil. The isolated material was immediately subjected to purification by flash chromatography on SiO₂ (20-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The semipure product (existed as a mixture of diastereomers heavily favoring the desired product) was subjected to crystallization from 3.5% dimethoxyethane in hexanes over several days. The resulting colorless crystals were washed with hexanes to provide (+)-TBZ compound 16 as a single diastereomer 42%: [α]²⁶ _(D) +40.1 (c 0.63, CH₂Cl₂); ¹H NMR (CD₂Cl₂) δ 1.14 (s, 9H), 1.18-1.30 (m, 1H), 1.45-1.56 (m, 2H), 1.60-1.75 (m, 2H), 1.86-1.98 (m, 1H), 2.41 (apparent t, J=11.4 Hz, 1H), 2.47 (apparent t, J=12.6 Hz, 1H), 2.59-2.82 (m, 3H), 2.93 (dd, J=13.1, 2.8 Hz, 1H), 3.06-3.20 (m, 2H), 3.34 (dd, J=9.6, 6.1 Hz, 1H), 3.55 (apparent d, J=11.6 Hz, 1H), 3.78 (apparent t, J=6.3 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.64 (s, 1H), 6.69 (s, 1H), 7.40-7.53 (m, 6H), 7.70-7.81 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.14, 23.43, 25.98, 26.74, 29.47, 32.77, 47.55, 49.42, 50.44, 55.74, 55.86, 61.06, 62.36, 63.81, 108.31, 111.68, 126.31, 127.68, 128.91, 129.60, 134.15, 135.59, 147.59, 147.90, 209.36; HRMS-(ESI+) calcd for (C₃₅H₄₅NO₄Si+H) [M+H]⁺ 572.3196, found 572.3187.

Method 12 Removal the Boc Protecting Group from First Intermediate 14 and Amino Cyclization Provide (+)-TBZ Compound 17

The starting material 14 (1.0 eq) was dissolved in 10% Me₂S-dichloromethane to provide a 176 mM solution of the starting material. The solution was cooled to 0° C. and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0° C.) was added to the reaction mixture to provide a final concentration of 88 mM. The reaction mixture was permitted to stir at 0° C. for 1 h. Following the allotted time the reaction mixture was quenched at 0° C. by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide a yellow foam. The crude product was purified by flash chromatography on SiO₂ (0.2% triethylamine-10% EtOAc-89.8% hexanes to 0.2% triethylamine-50% EtOAc-49.8% hexanes, elution was observed at 285 nm and 228 nm). The product (+)-TBZ compound 17 was a colorless foam consisting of only the desired diastereomer 73%: ¹H NMR (CD₂Cl₂) δ 0.79 (dd, J=13.8, 3.8 Hz, 1H), 0.92 (s, 6H), 1.14 (s, 9H), 1.59-1.72 (m, 2H), 2.27 (dd, J=13.2, 5.1 Hz, 1H), 2.52-2.65 (m, 2H), 2.68-2.82 (m, 2H), 2.94 (dd, J=13.0, 3.0 Hz, 1H), 3.06-3.18 (m, 2H), 3.25 (dd, J=9.8, 6.3 Hz), 3.55 (dd, J=11.6, 1.8 Hz, 1H), 3.83-3.88 (m, 8H), 6.65 (s, 1H), 6.69 (s, 1H), 7.44-7.53 (m, 6H), 7.74-7.82 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.09, 26.79, 27.10, 29.48, 32.31, 36.90, 44.38, 46.02, 47.45, 50.15, 55.77, 55.91, 61.09, 62.53, 63.50, 108.38, 111.75, 126.30, 127.74, 128.93, 129.67, 134.13, 135.65, 147.66, 147.98, 208.73; HRMS-(ESI+) calcd for (C₃₇H₄₉NO₄Si+H) [M+H]⁺ 600.3509, found 600.3499.

Method 13 Reduction of (+)-Tetrabenazine 15 to a Diasteromeric Mixture of Dihydrotetrabenazine Compounds 18 and 19

To a 0.11 M solution of (+)-TBZ (15) in ethanol at 0° C. was added NaBH₄ (2.85 eq). The reaction mixture was allowed to stir for 60 min. at room temperature. The solvent was carefully removed under reduced pressure, and the residue was taken up in dichloromethane and washed with three portions of saturated aqueous K₂CO₃. The aqueous washings were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a colorless oil that crystallized on standing under high vacuum. Purification of the crude product was achieved by chromatography on SiO₂ (2.5-5% MeOH—CH₂Cl₂, elution was observed at 285 nm) UV active fractions were reanalyzed by TLC. Two products, 18 and 19, were isolated from this procedure. The major product 18 was a colorless solid 74%: [α]²⁶ _(D) +48 (c 0.30, CH₂Cl₂) ¹H NMR (CD₂Cl₂) δ 0.93 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.04 (ddd, J=14.6, 8.7, 4.3 Hz, 1H), 1.42 (dd, J=20.2, 11.4 Hz, 1H), 1.59 (ddd, J=13.7, 9.6, 3.3 Hz, 1H), 1.64-1.78 (m, 2H), 1.96 (apparent t, J=11.4 Hz, 1H), 2.27 (br s, 1H), 2.40-2.48 (m, 1H), 2.54 (ddd, J=12.3, 3.7, 2.3 Hz, 1H), 2.60-2.67 (m, 1H), 2.95-3.09 (m, 3H), 3.11 (apparent d, J=11.1 Hz, 1H), 3.35 (ddd, J=10.4, 10.4, 4.5 Hz, 1H), 3.80-3.81 (m, 6H), 6.60 (s, 1H), 6.69 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 21.61, 24.02, 25.33, 29.30, 39.68, 40.81, 41.58, 51.83, 55.74, 55.91, 60.02, 60.92, 74.32, 108.42, 111.73, 126.68, 129.76, 147.35, 147.61; HRMS-(ESI+) calcd for (C₁₉H₂₉NO₃+H) [M+H]⁺ 320.2226, found 320.2242. The minor product 19 was a yellow oil 4%: ¹H NMR (CD₂Cl₂) δ 0.94 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.13-1.20 (m, 1H), 1.24-1.34 (m, 2H), 1.60-1.77 (m, 2H), 1.89-2.00 (m, 1H) 2.36-2.44 (m, 2H), 2.53 (ddd, J=10.5, 10.5, 3.8 Hz, 1H), 2.58-2.70 (m, 2H), 2.91-2.98 (m, 1H), 2.98-3.09 (m, 1H), 3.48 (apparent d, J=11.6 Hz, 1H), 3.80-3.82 (apparent s, 6H), 4.07 (apparent d, J=3.1 Hz, 1H), 6.60 (s, 1H), 6.68 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 22.74, 22.81, 24.87, 29.30, 37.83, 38.87, 39.42, 52.44, 55.76, 55.96, 56.32, 56.43, 67.88, 108.45, 111.78, 127.18, 130.38, 147.30, 147.54.

Method 14 Ketalization of TBZ Compound 16

To an 87 mM solution of the starting material 16, 1.0 eq) in ethylene glycol was added methane sulfonic acid (1.76 eq). The reaction mixture was heated to and maintained at 85° C. for 20 h in a sealed vessel. Following the allotted time, the reaction mixture was quenched be the addition of 1 mL of saturated aqueous potassium carbonate solution and EtOAc was added. The reaction mixture was stirred for an additional hour at room temperature after which time the aqueous and organic layers were partitioned and separated. The aqueous layer was extracted with three portions of CH₂Cl₂ and the combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow oil. Purification of the crude material was undertaken by flash chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-9% methanol-90% DCM; elution was observed at 284 nm and 240 nm). Pools believed to contain the desired product were collected to provide ketal 20 as a colorless oil 73%: ¹H NMR (CD₂Cl₂) δ 1.03-1.15 (m, 1H), 1.20-1.35 (m, 2H), 1.37-1.61 (m, 4H), 1.87-1.99 (m, 1H), 2.08-2.17 (br. s, 1H), 2.20-2.29 (m, 2H), 2.42-2.51 (m, 1H), 2.55-2.64 (m, 1H), 2.92-3.03 (m, 3H), 3.27 (apparent d, J=11 Hz, 1H), 3.57 (apparent t, J=6.3 Hz, 2H), 3.758 (s, 3H), 3.764 (s, 3H), 3.92-4.00 (m, 2H), 4.00-4.09 (m, 2H), 6.56 (s, 1H), 6.57 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 23.74, 25.30, 29.31, 33.25, 41.00, 43.90, 55.74, 56.07, 58.68, 59.82, 62.64, 63.68, 65.17, 63.35, 108.50, 109.65, 111.78, 126.82, 129.81, 147.31, 147.67; LRMS-(ESI+) calcd for (C₂₁H₃₁NO₅+H) [M+H]⁺ 378.23, found 378.25.

Method 15 Fluorination of Hydroxy Ketal 20

To a 100 mM solution of the starting hydroxy ketal 20 in dichloromethane was added DAST reagent (2.2 eq.) at room temperature. The reaction mixture was permitted to stir for 16 h after which time the reaction mixture was quenched by the addition of saturated aqueous NaHCO₃. The aqueous and organic layers were partitioned and separated, and the aqueous layer was extracted with three portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow oil that was purified by flash chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-5% methanol-94% DCM, 40CV; elution was observed at 284 nm and 240 nm). The purified product alpha-fluoroalkyl ketal 21 was obtained as a yellow oil in 60% yield. The isolated material was taken on to the next step without additional characterization.

Method 16 Preparation of Alpha-Fluoroalkyl Tetrabenazine Compound 22 Via Protected Tetrabenazine Compound Alpha-Fluororalkyl Ketal 21

To an 8 mM solution of the starting fluoroalkyl ketal 21 in 3:1 THF-water was added 0.18 g of DOWEX strongly acidic cation exchange resin. The reaction mixture was heated to and maintained at 65° C. overnight. The resin was washed with saturated aqueous potassium carbonate and the mixture was extracted with three portions of dichloromethane and three portions of toluene. The organic extracts were combined, dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude material was purified by semi-preparative HPLC on a Phenomenex Gemini C₁₈ column 5 μm, (4.6×250 mm; UV @ 284 nm and 240 nm) at a Flow rate of 1.0 mL/min. The following gradient was used: 100% 0.1 mM TEAA buffer pH 7.0 and holding for 3 min. then ramping to 98% MeCN 2% 0.1 mM TEAA buffer pH 7.0 over 25 min and finally holding at this level for an additional 12 min. The column was maintained at room temperature during the analysis. The major UV active peak eluted at 34.8 min and was collected and concentrated under reduced pressure to provide the product as a yellow oil 5%: LRMS-(ESI+) calcd for (C₁₉H₂₆FNO₃+H) [M+H]⁺ 336.20, found 336.16.

Method 17 Preparation of Dihydrotetrabenazine Compound 23

To a 0.1 M solution of tetrabenazine compound 16 in ethanol at 0° C. was added NaBH₄ (2.85 eq). The reaction mixture was allowed to stir for 60 min. at room temperature. The excess solvent was carefully removed under reduced pressure, and the residue was taken up in dichloromethane and washed with three portions of saturated aqueous K₂CO₃. The aqueous washings were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow foam. Purification of the crude product was achieved by chromatography on SiO₂ (2.5-5% MeOH—CH₂Cl₂, elution was observed at 285 nm). The product dihydrotetrabenazine compound 23 was a colorless foam 78%: ¹H NMR (CD₂Cl₂) δ 1.09-1.22 (m, 11H), 1.44 (dd, J=20.1, 11.6 Hz, 2H), 1.55-1.72 (m, 4H), 1.78-1.88 (m, 1H), 2.02 (apparent t, J=11.4 Hz, 1H), 2.46 (ddd, J=4.6, 11.3, 10.3 Hz, 1H), 2.57 (ddd, J=13.1, 3.8, 2.5 Hz, 1H), 2.65 (dd, J=14.3, 4.0 Hz, 1H), 2.94-3.10 (m, 3H), 3.14 (apparent d, J=11.1 Hz, 1H), 3.40 (ddd, J=9.5, 9.5, 4.6 Hz, 1H), 3.76 (apparent t, J=6.3 Hz, 2H), 3.83 (apparent s, 6H), 6.63 (s, 1H), 6.73 (s, 1H), 7.42-7.49 (m, 6H), 7.71-7.76 (m, 4H), ¹³C NMR (CD₂Cl₂) δ 19.17, 23.21, 26.75, 29.38, 29.79, 33.03, 40.89, 43.88, 51.86, 55.76, 55.94, 59.78, 60.95, 63.93, 73.92, 108.48, 111.76, 126.75, 127.69, 129.61, 129.81, 134.23, 135.62, 147.38, 147.63; HRMS-(ESI+) calcd for (C₃₅H₄₇NO₄Si+H) [M+H]⁺ 574.3353, found 574.3333.

Method 18 Preparation of Dihydrotetrabenazine Compound 24 and 2-epi-24

To a 0.1 M solution of tetrabenazine compound 17 in ethanol at 0° C. was added NaBH₄ (2.85 eq). The reaction mixture was allowed to stir for 60 min. at room temperature. The excess solvent was carefully removed under reduced pressure, and the residue was taken up in dichloromethane and washed with three portions of saturated aqueous K₂CO₃. The aqueous washings were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow foam. Purification of the crude product dihydrotetrabenazine compound 24 was achieved by chromatography on SiO₂ (2.5-5% MeOH—CH₂Cl₂, elution was observed at 285 nm). The product 24 was a colorless foam 69%: ¹H NMR (CD₂Cl₂) δ 0.99 (s, 6H), 1.02-1.06 (m, 1H), 1.16 (s, 9H), 1.48 (dd, J=20.2, 11.4 Hz, 1H), 1.63-1.82 (m, 4H), 2.06 (apparent t, J=11.4 Hz, 1H), 2.47 ((ddd, J=3.8, 10.6, 10.6 Hz, 1H), 2.60 (ddd, J=12.0, 3.4, 2.3 Hz, 1H), 2.68 (apparent br d, J=15.4 Hz, 1H), 2.96-3.04 (m, 1H), 3.05-3.14 (m, 2H), 3.17 (apparent br d, J=11.4 Hz, 1H), 3.31 (ddd, J=9.3, 9.3, 4.3 Hz, 1H), 3.85 (s, 6H), 3.87-3.92 (m, 2H), 6.66 (s, 1H), 6.75 (s, 1H), 7.43-7.56 (m, 6H), 7.76-7.86 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.10, 26.83, 27.67, 27.77, 29.28, 32.73, 39.98, 40.64, 42.21, 44.66, 49.89, 51.75, 55.77, 55.94, 61.02, 61.24, 62.71, 73.88, 108.46, 111.79, 126.62, 127.76, 129.70, 134.10, 135.68, 147.44, 147.69. A small amount of the ring position-2 epimer of dihydrotetrabenazine compound 24 was isolated in about 12% yield and was characterized. The epimeric product, 2-epi-24, was a pale yellow oil: ¹H NMR (CD₂Cl₂) δ 0.92 (s, 6H), 0.96-1.02 (m, 2H), 1.08 (s, 9H), 1.42 (dd, J=14.5, 4.7 Hz, 1H), 1.61-1.71 (m, 3H), 1.86-1.95 (m, 1H), 2.35 (apparent dt, J=13.7, 2.9 Hz, 1H), 2.43 (apparent t, J=11.6 Hz, 1H), 2.51 (ddd, J=11.4, 11.4, 3.9 Hz, 1H), 2.59-2.67 (m, 2H), 2.88-2.95 (m, 1H), 2.98-3.11 (m, 1H), 3.45 (br d, J=11.4 Hz, 1H), 3.76-3.88 (m, 8H), 3.94-4.01 (m, 1H), 6.61 (s, 1H), 6.67 (s, 1H), 7.40-7.54 (m, 6H), 7.68-7.81 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.05, 26.72, 27.51, 29.31, 29.78, 32.81, 36.51, 39.36, 41.99, 44.53, 52.34, 55.77, 55.86, 55.96, 57.71, 61.16, 69.62, 108.45, 111.80, 127.19, 127.71, 129.64, 130.43, 134.12, 135.65, 147.30, 147.53. The minor epimer, 2-epi-24, was converted by a series of steps analogous to Method steps 19 (protection of the hydroxy methine group as a THP ether to provide 2-epi-26), 21 (removal of the t-butyldiphenylsilyl group to provide 2-epi-28), and 23 (reaction of the primary hydroxy group with DAST to provide 2-epi-30); and then removal of the THP ether protecting group in a step analogous to that described in Example 3 to provide the alpha-fluoroalkyl dihydrotetrabenazine 2-epi-32 (See Table 15), a compound identical in structure to compound 32 in all respects save the configuration at ring position-2 which is “S” rather than “R”. The intermediate 2-epi-28 was characterized by low resolution mass spectroscopy: LRMS-(ESI+) calcd for (C₂₄H₃₇NO₅+H) [M+H]⁺ 448.31, found 448.26. Alpha-fluoroalkyl dihydrotetrabenazine 2-epi-32 was characterized by high resolution mass spectroscopy: HRMS-(ESI+) calcd for (C₂₁H₃₂FNO₃+H) [M+H]⁺ 366.24445, found 366.24333.

Method 19 Preparation of THP Protected DTBZ Compound 25

To a 0.1M solution of the starting dihydrotetrabenazine compound 23 (1.0 eq) in dichloromethane was added methane sulfonic acid (1.1 eq), followed by dihydropyran (2.2 eq.). The reaction was permitted to stir at 26° C. for 36 h. Following this time, the reaction mixture was quenched by the addition of saturated aqueous potassium carbonate solution. Dichloromethane was added, and the aqueous and organic layers were partitioned and separated. The aqueous layer was extracted with three portions of CH₂Cl₂, and the combined organic extracts were dried, (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow oil that was immediately subjected to purification by flash chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-5% methanol-94% DCM; elution was observed at 284 nm and 240 nm). Fractions presumed to contain the desired product were concentrated under reduced pressure to provide protected dihydrotetrabenazine compound 25 as a pale yellow oil that existed as a roughly 1:1 mixture of diastereomers 75%: ¹H NMR (CD₂Cl₂) δ 1.10 (s, 9H), 1.48-1.65 (m, 8H), 1.66-1.79 (m, 4H), 1.80-1.90 (m, 1.5H), 1.91-1.99 (m, 0.5H), 1.99-2.11 (m, 1H), 2.40-2.51 (m, 1H), 2.62-2.68 (m, 1H), 2.68-2.76 (m, 1H), 2.95-3.16 (m, 3H), 3.29-3.37 (m, 0.5H), 3.49-3.58 (m, 1.5H), 3.71-2.78 (dd, J=9.4, 6.1 Hz, 2H); 3.79-3.86 (m, 6H), 3.86-3.94 (m, 1H), 3.95-4.07 (m, 1H), 4.65-4.71 (m, 0.5H), 4.92-5.01 (m, 0.5H), 6.60-6.64 (s, 1H), 6.69-6.72 (s, 0.5H), 6.72-6.75 (s, 0.5H), 7.39-7.50 (m, 6H), 7.68-7.77 (m, 4H); ¹³C NMR (CD₂Cl₂) δ 19.16, 19.69, 20.24, 23.17, 23.23, 25.65, 25.67, 25.72, 26.74, 29.43, 29.46, 29.78, 29.90, 30.69, 31.14, 31.21, 33.06, 33.11, 36.00, 39.52, 41.61, 42.49, 51.77, 51.95, 55.76, 56.04, 56.17, 59.91, 59.99, 60.72, 61.00, 62.31, 62.50, 62.87, 63.96, 64.10, 75.58, 82.46, 94.06, 101.79, 108.75, 108.80, 111.76, 111.82, 126.83, 126.98, 127.68, 129.58, 130.00, 130.04, 134.23, 134.25, 134.26, 134.28, 135.61, 147.35, 147.38, 147.68, 147.71

Method 20 Preparation of THP Protected DTBZ Compound 26

To a 0.1M solution of the starting dihydrotetrabenazine compound 24 (1.0 eq) in dichloromethane was added methane sulfonic acid (1.1 eq), followed by dihydropyran (2.2 eq.). The reaction was permitted to stir at 26° C. for 36 h. Following this time, the reaction mixture was quenched be the addition of saturated aqueous potassium carbonate solution. Dichloromethane was added, and the aqueous and organic layers were partitioned and separated. The aqueous layer was extracted with three portions of CH₂Cl₂, and the combined organic extracts were dried, (MgSO₄), filtered, and concentrated under reduced pressure to provide protected dihydrotetrabenazine compound 26 as a yellow foam that existed as a roughly 1:1 mixture of diastereomers the crude product was taken on to the next step without additional purification 99%.

Method 21 Preparation of Alpha-Hydroxyalkyl Protected Dihydrotetrabenazine Compound 27

To a 0.3 M solution of the protected dihydrotetrabenazine compound 25 in THF was added a 1.0 M tetrabutylammonium fluoride (TBAF) solution in THF (3.3 eq) bringing the final reaction concentration to 0.15 M with respect to the starting material 25. The reaction mixture was allowed to continue stirring at room temperature for 14 h. The mixture was diluted with deionized water, and extracted with three portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow oil. The crude material was purified by column chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-10% methanol-89% DCM; elution was observed at 284 nm and 240 nm). The product alpha-hydroxyalkyl protected dihydrotetrabenazine compound 27 eluted late in the run as a broad peak. The product was a 1:1 mixture of diastereomers that presented as a pale yellow oil 60%: ¹H NMR (CD₂Cl₂) δ 1.11-1.33 (m, 2.0H), 1.48-1.66 (m, 8.0H), 1.69-1.80 (m, 2.5H), 1.81-1.95 (1.5H), 1.98-2.13 (m, 1.0H), 2.21-2.38 (m, 1.0H), 2.40-2.52 (m, 1.0H), 2.58-2.67 (m, 1.5H), 2.70 (ddd, J=12.5, 3.8, 2.5 Hz, 0.5H), 2.95-3.15 (m, 4.0H), 3.33 (ddd, J=9.5, 9.5, 4.5 Hz, 0.5H), 3.51-3.59 (m, 1.5H), 3.62 (apparent dd, J=9.7, 6.3 Hz, 2.0H), 3.81 (apparent s, 4.5H), 3.82 (s, 1.5H), 3.82-3.96 (m, 0.5H), 3.97-4.04 (m, 0.5H), 4.69 (dd, J=3.6, 2.8 Hz, 0.5H), 4.89-4.94 (m, 0.5H), 6.60 (apparent d, J=1.8 Hz, 1.0H), 6.70 (apparent d, J=3.5 Hz, 1.0H); ¹³C NMR (CD₂Cl₂) δ 19.99, 20.19, 22.91, 23.16, 25.64, 25.66, 29.28, 29.32, 29.71, 29.78, 31.13, 31.32, 33.13, 33.24, 35.96, 39.35, 41.38, 42.32, 51.66, 51.85, 55.74, 56.01, 56.16, 59.82, 59.93, 60.68, 60.95, 62.32, 62.55, 62.83, 62.86, 75.96, 82.35, 94.72, 101.75, 108.71, 108.74, 111.71, 111.78, 126.71, 126.89, 129.78, 129.82, 147.34, 147.37, 147.69, 147.73; LRMS-(ESI+) calcd for (C₂₄H₃₇NO₅+H) [M+H]⁺ 448.31, found 448.25.

Method 22 Preparation of Alpha-Hydroxyalkyl Protected Dihydrotetrabenazine Compound 28

To a 0.3 M solution of the doubly protected dihydrotetrabenazine compound 26 in THF was added a 1.0 M TBAF solution in THF (3.3 eq) bringing the final reaction concentration to 0.15 M with respect to the starting material 26. The reaction mixture was allowed to continue stirring at room temperature for 14 h. The mixture was diluted with deionized water, and extracted with three portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide a yellow oil. The crude material was purified by column chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-10% methanol-89% DCM; elution was observed at 284 nm and 240 nm). The product eluted late in the run as a broad peak. The product alpha-hydroxyalkyl protected dihydrotetrabenazine compound 28 was a 1:1 mixture of diastereomers that presented as a colorless oil 71%: ¹H NMR (CD₂Cl₂) δ 0.90-1.10 (m, 6.5H), 1.23-1.39 (m, 0.5H), 1.48-1.69 (m, 7.0H), 1.71-1.94 (m, 4.0H), 2.08 (m, 1.0H), 2.38-2.83 (m, 4.0H), 2.93-3.16 (m, 3.5H), 3.22 (ddd, J=9.5, 9.5, 4.5 Hz, 0.5H), 3.40-3.60 (m, 1.5H), 3.61-3.76 (m, 2.0H), 3.77-3.91 (m, 6H), 3.92-4.06 (m, 1.5H), 4.62-4.83 (m, 0.5H), 4.83-5.09 (m, 0.5H), 6.60 (apparent d, J=1.8 Hz, 1.0H), 6.70 (apparent d, J=3.5 Hz, 1.0H); ¹³C NMR (CD₂Cl₂) δ 19.96, 25.67, 27.62, 27.71, 27.89, 29.26, 29.30, 31.18, 31.28, 32.78, 35.87, 37.52, 38.28, 39.34, 41.47, 41.95, 45.18, 45.29, 51.50, 51.74, 55.72, 55.99, 56.15, 59.12, 59.19, 60.60, 60.85, 62.58, 62.71, 62.82, 62.94, 76.16, 83.14, 94.56, 102.07, 108.75, 111.73, 111.81, 126.69, 126.86, 129.86, 129.93, 147.33, 147.37, 147.67, 147.73; LRMS-(ESI+) calcd for (C₂₆H₄₁NO₅+H) [M+H]⁺ 448.31, found 448.25.

Example 1 Preparation of Alpha-Fluoroalkyl Protected Dihydrotetrabenazine Compound 29

To a 60 mM solution of the starting alpha-hydroxyalkyl protected dihydrotetrabenazine compound 27 in dichloromethane was added diethylaminosulfur trifluoride (DAST, 2.2 eq.) at room temperature. The reaction was stirred for 14 h at this temperature, and then quenched by the addition of saturated aqueous potassium carbonate solution. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide an orange oil that was purified by flash chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-10% methanol-89% DCM, 40CV; elution was observed at 284 nm and 240 nm). The desired product eluted as a broad peak, late in the run. The product alpha-fluoroalkyl protected dihydrotetrabenazine compound 29 was a pale yellow oil that existed as a 1:1 mixture of diastereomers 58%: ¹H NMR (CD₂Cl₂) δ 1.12-1.31 (m, 2.0H), 1.50-1.67 (m, 6.0H), 1.66-1.91 (m, 6.0H), 1.99-2.12 (m, 1.0H), 2.39-2.51 (m, 1.0H), 2.59-2.67 m, 1.5H), 2.71 (ddd, J=12.5, 3.8, 2.5 Hz, 0.5H), 2.93-3.15 (m, 4.0H), 3.33 (ddd, J=9.3, 9.3, 4.5 Hz, 0.5H), 3.49-3.59 (m, 1.5H), 3.76-3.87 (m, 6.0H), 3.88-3.94 (m, 0.5H), 3.97-4.04 (m, 0.5H), 4.42 (ddd, J=6.1, 4.3, 6.1 Hz, 1.0H), 4.54 (ddd, J=6.1, 4.3, 6.1 Hz, 1.0H), 4.66-4.74 (m, 0.5H), 4.91-4.99 (m, 0.5H), 6.56-6.66 (m, 1.0H), 6.68-6.78 (m, 1.0H); ¹³C NMR (CD₂Cl₂) δ 19.79, 20.22, 22.60, 22.63, 22.66, 22.69, 25.66, 25.72, 29.42, 29.46, 29.65, 29.76, 30.73, 30.79, 30.92, 30.98, 31.15, 31.25, 36.02, 39.50, 41.57, 42.41, 51.75, 51.93, 55.76, 56.04, 56.17, 59.88, 59.96, 60.70, 60.97, 62.49, 62.89, 75.83, 82.45, 83.39, 83.49, 85.01, 85.12, 94.29, 101.76, 108.75, 108.79, 111.75, 111.82, 126.83, 126.99, 129.96, 130.01, 147.35, 147.38, 147.67, 147.72; LRMS-(ESI+) calcd for (C₂₄H₃₆FNO₄+H) [M+H]⁺ 422.27, found 422.23.

Example 2 Preparation of Alpha-Fluoroalkyl Protected Dihydrotetrabenazine Compound 30

To a 60 mM solution of the starting alpha-hydroxyalkyl protected dihydrotetrabenazine compound 28 in dichloromethane was added diethylaminosulfur trifluoride (DAST, 2.2 eq.) at room temperature. The reaction was stirred for 14 h at this temperature, and then quenched by the addition of saturated aqueous potassium carbonate solution. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure to provide an orange oil that was purified by flash chromatography on SiO₂ (1% triethylamine-DCM to 1% triethyamine-10% methanol-89% DCM, 40CV; elution was observed at 284 nm and 240 nm). The desired product eluted as a broad peak, late in the run. The product alpha-fluoroalkyl protected dihydrotetrabenazine compound 30 was an oil that existed as a 1:1 mixture of diastereomers 46%. The isolated material was taken on to the next step without additional characterization or analysis.

Method 23 Preparation of Alpha-Fluoroalkyl Dihydrotetrabenazine Compound 31

The starting material, alpha-fluoroalkyl protected dihydrotetrabenazine compound 29, was dissolved in 0.1 M HCl in MeOH to provide a 26 mM solution of the starting material 29. The reaction mixture was permitted to stir for 1.5 h at room temperature. The solvent was removed under reduced pressure, and the residue was dried under high vacuum for one hour. The residue was treated with aqueous potassium carbonate solution and extracted with three portions of dichloromethane. The dichloromethane extracts were dried, (MgSO₄) filtered, and concentrated under reduced pressure to provide the desired product alpha-fluoroalkyl dihydrotetrabenazine 31 as a colorless solid 99%: ¹H NMR (CD₂Cl₂) δ 1.15-1.26 (m, 1H), 1.47 (m, 2H), 1.54-1.91 (m, 6H), 2.05 (apparent t, J=11.4 Hz, 1H), 2.43-2.51 (m, 1H), 2.56 (ddd, J=12.3, 3.8, 2.5 Hz, 1H), 2.60-2.68 (m, 1H), 2.96-3.09 (m, 3H), 3.15 (apparent d, J=11.1 Hz, 1H), 3.42 (ddd, J=9.5, 9.5, 4.6 Hz, 1H), 3.81 (s, 6H), 4.42 (t, J=6.1 Hz, 1H), 4.54 (t, J=6.1 Hz, 1H), 6.61 (s, 1H), 6.70 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 22.80 (d_(C*—C—C—F), J=5.1 Hz), 29.41, 29.80, 30.99 (d_(C*—C—F), J=19.0 Hz), 41.02, 43.91, 51.93, 55.90, 56.07, 59.79, 61.05, 74.00, 84.36 (d_(C*—F), J=163.2 Hz), 108.58, 111.88, 126.79, 129.68, 147.55, 147.82; LRMS-(ESI+) calcd for (C₁₉H₂₈FNO₃+H) [M+H]⁺ 338.21, found 338.20.

Method 24 Preparation of Alpha-Fluoroalkyl Dihydrotetrabenazine Compound 32

The starting material was dissolved in 0.1 M HCl in MeOH to provide a 26 mM solution of the starting material 30. The reaction mixture was permitted to stir for 1.5 h at room temperature. The solvent was removed under reduced pressure, and the residue was dried under high vacuum for one hour. The residue was treated with aqueous potassium carbonate solution and extracted with three portions of dichloromethane. The dichloromethane extracts were dried, (MgSO₄) filtered, and concentrated under reduced pressure to provide the desired product alpha-fluoroalkyl dihydrotetrabenazine 32 as colorless solid 99%: ¹H NMR (CD₂Cl₂) δ 0.92-0.97 (m, 1H), 1.01 (s, 6H), 1.03-1.11 (m, 1H), 1.42 (q, J=11.4 Hz, 1H), 1.62-1.85 (m, 1H), 2.06 (t, J=11.4 Hz, 1H), 2.39-2.49 (m, 1H), 2.57 (ddd, J=12.3, 3.8, 2.5 Hz, 1H), 2.60-2.68 (m, 1H), 2.94-3.08 (m, 3H), 3.14 (apparent d, J=11.1 Hz, 1H), 3.33 (ddd, J=9.5, 9.5, 4.6 Hz, 1H), 3.81 (s, 6H), 4.54 (ddd, 6.2, 6.2, 2.0 Hz, 1H), 4.66 (ddd, 6.2, 6.2, 1.8 Hz, 1H), 6.60 (s, 1H), 6.69 (s, 1H); ¹³C NMR (CD₂Cl₂) δ 27.47, 27.65, 29.33, 32.65 (d_(C*—C—C—F), J=4.4 Hz), 40.09, 40.87, 42.07 (d_(C*—C—F), J=17.6 Hz), 42.09, 51.75, 55.78, 55.94, 60.94, 62.64, 74.09, 82.16 (d_(C*—F), J=161.7 Hz), 108.40, 111.76, 126.69, 129.73, 147.42, 147.66; HRMS-(ESI+) calcd for (C₂₁H₃₂FNO₃+H) [M+H]⁺ 366.24445, found 366.24404.

Method 25 Preparation of Fluorophilic Protected Tetrabenazine Tosylate 33 Via Intermediate Protected Tetrabenazine Alcohol 20.

To a solution of alpha-hydroxyalkyl protected TBZ compound 20 in pyridine is added toluene sulfonyl chloride (tosyl chloride 1.5 equivalents) and the mixture is stirred at 0° C. and periodically monitored by thin layer chromatography (tlc). When tlc indicates complete consumption of the starting alcohol 20, the reaction mixture is quenched by adding ice-cold water and EtOAc. The organic layer is washed successively with water, 1M HCl (5×), saturated Na₂CO₃ and brine. The organic layer is dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel to afford fluorophilic protected TBZ tosylate 33.

Method 26 Preparation of Fluorophilic Protected Tetrabenazine Tosylate 34 Via Intermediate Protected Tetrabenazine Alcohol 27

To a solution of alpha-hydroxyalkyl protected TBZ compound 27 in pyridine is added toluene sulfonyl chloride (tosyl chloride 1.5 equivalents) and the mixture is stirred at 0° C. and periodically monitored by thin layer chromatography (tlc). When tlc indicates complete consumption of the starting alcohol 20, the reaction mixture is quenched by adding ice-cold water and EtOAc. The organic layer is washed successively with water, 1M HCl (5×), saturated Na₂CO₃ and brine. The organic layer is dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel to afford fluorophilic protected TBZ tosylate 34.

Method 27 Preparation of PET Imaging Agent 35

To a Teflon-lined reaction vial contained in a shielded hood and fitted with a nitrogen purge inlet and magnetic spin bar, is added about 1 milliliter of an aqueous acetonitrile solution F-18 fluoride ion, potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). The vial is heated at 100° C. under a stream of nitrogen to effect the azeotropic removal of water. Additional dry acetonitrile (1 mL) is added and evaporated. This azeotropic drying protocol is repeated three times. After the final evaporation step a mixture of dimethyl formamide and acetonitrile (about 1 mL) containing fluorophilic protected TBZ tosylate 33 (2 mg) is added and the vial is sealed. The reaction mixture is stirred and heated at 100° C. for 10 minutes and then is cooled to room temperature. The product mixture comprising the starting tosylate 33 and the product F-18 alpha-fluoroalkyl protected tetrabenazine is diluted with water (10 mL) and applied to a Sep-Pak cartridge. The cartridge is then washed with water (3×) to remove unreacted fluoride ion and other water soluble components of the product mixture. The radiolabled alpha-fluoroalkyl protected tetrabenazine compound and starting tosylate 33 are then eluted from the cartridge with acetonitrile. Most of the acetonitrile is then evaporated and the residue is dissolved in aqueous methanol containing hydrochloric acid (HCl) and heated at 60° C. The mixture is again concentrated and subjected to preparative reverse phase HPLC to afford an aqueous formulation comprising PET imaging agent 35.

Method 28 Preparation of PET Imaging Agent 36

To a Teflon-lined reaction vial contained in a shielded hood and fitted with a nitrogen purge inlet and magnetic spin bar, is added about 1 milliliter of an aqueous acetonitrile solution F-18 fluoride ion, potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). The vial is heated at 100° C. under a stream of nitrogen to effect the azeotropic removal of water. Additional dry acetonitrile (1 mL) is added and evaporated. This azeotropic drying protocol is repeated three times. After the final evaporation step a mixture of dimethyl formamide and acetonitrile (about 1 mL) containing fluorophilic protected DTBZ tosylate 34 (2 mg) is added and the vial is sealed. The reaction mixture is stirred and heated at 100° C. for 10 minutes and then is cooled to room temperature. The product mixture comprising the starting tosylate 34 and the intermediate F-18 alpha-fluoroalkyl protected dihydrotetrabenazine is diluted with water (10 mL) and applied to a Sep-Pak cartridge. The cartridge is then washed with water (3×) to remove unreacted fluoride ion and other water soluble components of the product mixture. The radiolabled alpha-fluoroalkyl intermediate and starting tosylate 34 are then eluted from the cartridge with acetonitrile. Most of the acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and treated with DOWEX strongly acidic cation exchange resin at 65° C. for 10 minutes. The reaction mixture is then filtered and subjected to preparative reverse phase HPLC to afford an aqueous formulation comprising PET imaging agent 36.

Method 29 Alternate Preparation of PET Imaging Agent 36

To a Teflon-lined reaction vial contained in a shielded hood and fitted with a nitrogen purge inlet and magnetic spin bar, is added about 1 milliliter of an aqueous acetonitrile solution F-18 fluoride ion, potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). The vial is heated at 100° C. under a stream of nitrogen to effect the azeotropic removal of water. Additional dry acetonitrile (1 mL) is added and evaporated. This azeotropic drying protocol is repeated three times. After the final evaporation step a mixture of dimethyl formamide and acetonitrile (about 1 mL) containing fluorophilic tosylate 34 (2 mg) is added and the vial is sealed. The reaction mixture is stirred and heated at 100° C. for 10 minutes and then is cooled to room temperature. The product mixture comprising the starting tosylate 34 and the product F-18 alpha-fluoroalkyl protected dihydrotetrabenazine intermediate is concentrated under a stream of nitrogen and the residue is dissolved in ethanol containing HCl and the mixture is warmed briefly to effect removal of the THP protecting group. Excess octadecyl amine (5 mg) and potassium carbonate (2 mg) are then added and the mixture is heated for 5 minutes at 60° C. to convert unreacted tosylate groups to the corresponding octadecyl amine. The product mixture is then diluted with water (10 mL) and applied to a Sep-Pak cartridge. The cartridge is then washed with water (3×) to remove unreacted fluoride ion and other water soluble components of the product mixture. The radiolabled alpha-fluoroalkyl compound 36 and the corresponding octadecyl amine adduct 37 are then eluted from the cartridge with acetonitrile. Most of the acetonitrile is then evaporated and the residue is dissolved in aqueous acetonitrile and subjected to preparative reverse phase HPLC to provide purified PET imaging agent 36.

Measurement of Binding Affinity of Alpha-Fluoroalkyl Compounds 31, 32, 2-epi-32, (+) DTBZ 18, and Fluoroalkyl Tetrabenazine Carbinol Compounds 38 and 39 to VMAT-2

VMAT-2 binding affinities were measured for alpha-fluoroalkyl dihydrotetrabenazine compounds 31, 32, 2-epi-32 (+) DTBZ 18, and fluoroalkyl tetrabinazine carbinol compound 39 each of which bears a free hydroxyl group at ring position-2 (See Entries 9a-d and 9f of Table 9). In addition, the VMAT-2 binding affinity of a fluoroalkyl tetrabinazine carbinol compound 38 bearing an acetoxy group at ring position-2 was also measured. VMAT-2 binding affinity measurements were carried out by Novascreen Biosciences Corporation (Hanover, Md., USA) using protocol Cat. No. 100-0751. Novascreen, Inc. is a commercial provider of biological assays for the pharmaceutical industry. Binding affinity data are presented in Table 9 and illustrate very high binding affinity for the alpha-fluoroalkyl compounds 31, 2-epi-32, and 32 relative to a (+)-DTBZ control (Compound 18) and somewhat lower yet still robust binding activity for fluoroalkyl tetrabinazine carbinol compounds 38 and 39. The data obtained for alpha-fluoroalkyl compounds 31, 32 and 2-epi-32 reveal an unexpected tolerance of fluoroalkyl substitution at ring position-3, a structural change relative to TBZ and DTBZ which combines a change in the size and lipophilicity of the group at ring position-3 with the uncertainty which arises whenever a hydrogen in a biologically active molecule is replaced by fluorine. In addition, the binding constants Ki expressed in nano-molar (nM) concentration units indicate a very high affinity of the alpha-fluoroalkyl compounds of the present invention for the VMAT-2 biomarker. The data obtained for fluoroalkyl tetrabenazine carbinol compounds 38 and 39 illustrate a similar structure-activity principle, namely an unexpected tolerance of fluoroalkyl substitution at ring position-2, as well as the unexpected tolerance for substitution at the hydroxy group at ring position-2. The ensemble of the VMAT-2 binding data gathered for compounds 31, 32 and 2-epi-32 with the VMAT-2 binding data gathered for compounds 38 and 39 supports the proposition that alpha-fluoroalkyl dihydrotetrabenazine compounds having structure I and provided by the present invention will also bind to VMAT-2 and serve as useful positron emission tomography (PET) imaging agents in studies targeting the VMAT-2 biomarker.

TABLE 9 VMAT-2 Binding Affinity of Alpha-Fluoroalkyl Compounds 31, 32 and 2-epi-32, (+) DTBZ 18, and Fluoroalkyl Tetrabenazine Carbinol Compounds 38 and 39 Compound Entry No. Structure Ki (nM) 9a 31

6.4 9b 2-epi-32

2.6 9c 32

0.45 9d (+)-DTBZ (18)

3.0 9e 38

19 9f 39

19

Example 3 Preparation of (2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl acetate 40

To a solution of 10 mg (27 μmol) of alpha-fluoroalkyl dyhydrotetrabenazine compound 32 in 250 μL of anhydrous dichloromethane at 0° C. is added 4.4 μL (2 equiv., 54 μmol) of anhydrous pyridine followed by 3.1 μL (1.2 equiv., 32.4 μmol) of acetic anhydride. The reaction mixture is allowed to continue stirring, slowly warming to room temperature over 14 h. The progress of the reaction is followed by HPLC-MS. The reaction mixture is then quenched by the addition of 1 mL of saturated aqueous ammonium chloride solution and then diluted with an additional 750 μL of dichloromethane. The aqueous and organic layers are partitioned and separated, and the aqueous layer is extracted with two additional 1 mL portions of dichloromethane. The combined organic extracts are washed with 3 mL of brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to provide crude alpha-fluoroalkyl dihydrotetrabenazine acetate 40 that may be purified by preparative reversed phase HPLC.

Example 4 (2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl isobutyrate 41

To a solution of 10 mg (27 μmol) of alpha-fluoroalkyl dyhydrotetrabenazine compound 32 in 250 μL of anhydrous dichloromethane at 0° C. is added 4.4 μL (2 equiv., 54 μmol) of anhydrous pyridine followed by 5.4 μL (1.2 equiv., 32.4 μmol) of isobutyric anhydride. The reaction mixture is allowed to continue stirring, slowly warming to room temperature over 14 h. The progress of the reaction is followed by HPLC-MS. The reaction mixture is then quenched by the addition of 1 mL of saturated aqueous ammonium chloride solution and then diluted with an additional 750 μL of dichloromethane. The aqueous and organic layers are partitioned and separated, and the aqueous layer is extracted with two additional 1 mL portions of dichloromethane. The combined organic extracts are washed with 3 mL of brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to provide crude alpha-fluoroalkyl dihydrotetrabenazine isobutyrate 41 that may be purified by preparative reversed phase HPLC.

Example 5 (2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl benzylcarbamate 42

To a solution of 10 mg (27 μmol) of alpha-fluoroalkyl dyhydrotetrabenazine compound 32 in 250 μL of anhydrous dichloromethane at 0° C. is added 4.4 μL (2 equiv., 54 μmol) of anhydrous pyridine followed by 4.0 μL (1.2 equiv., 32.4 μmol) of benzyl isocyanate. The reaction mixture is allowed to continue stirring, slowly warming to room temperature over 14 h. The progress of the reaction is followed by HPLC-MS. The reaction mixture is then quenched by the addition of 1 mL of saturated aqueous ammonium chloride solution and then diluted with an additional 750 μL of dichloromethane. The aqueous and organic layers are partitioned and separated, and the aqueous layer is extracted with two additional 1 mL portions of dichloromethane. The combined organic extracts are washed with 3 mL of brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to provide crude alpha-fluoroalkyl dihydrotetrabenazine N-benzylcarbamate 42 that may be purified by preparative reversed phase HPLC.

Example 6 (2R,3R,11bR)-3-(4-fluoro-2,2-dimethylbutyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl carbamate 43

A suspension of triphosgene (3.9 mg, 13.2 μmol) in 150 μL of carbon tetrachloride and 2.6 μL (1.2 equiv., 32.4 μmol) of anhydrous pyridine is added to a stirred solution of 10 mg (27 μmol) of alpha-fluoroalkyl dyhydrotetrabenazine compound 32 in 150 μL of carbon tetrachloride. The resulting solution is stirred in a sealed vessel at 55-60° C. for 6 h. Following the allotted time the reaction mixture is cooled to room temperature, and the mixture is diluted with 250 μL of dichloromethane. The mixture is washed with two 200 μL portions of water and one 200 μL portion of brine, dried (Na₂SO₄), and concentrated under reduced pressure to provide the crude chloroformate. The crude material is dissolved in 60 μL of THF and is cooled in an ice bath. To this solution is added 60 μL of a 50% aqueous ammonia solution with vigorous stirring. The reaction mixture is allowed to continue stirring, slowly warming to room temperature over 14 h. Excess ammonia is removed under a stream of dry nitrogen. The residue is taken up in 2 mL of dichloromethane and washed with 1 mL of brine. The organic layer is collected, and the aqueous layer is washed with an additional 1 mL portion of dichloromethane. The organic extracts are, dried (Na₂SO₄), and concentrated under reduced pressure to provide crude alpha-fluoroalkyl dihydrotetrabenazine carbamate 43 that may be purified by preparative reversed phase HPLC.

Example 7 Preparation of PET Imaging Agent 45

To a Teflon-lined reaction vial contained in a shielded hood and fitted with a nitrogen purge inlet and magnetic spin bar, is added about 1 milliliter of an aqueous acetonitrile solution F-18 fluoride ion, potassium carbonate (about 1 mg), and Kryptofix 221 (about 10 mg). The vial is heated at 100° C. under a stream of nitrogen to effect the azeotropic removal of water. Additional dry acetonitrile (1 mL) is added and evaporated. This azeotropic drying protocol is repeated three times. After the final evaporation step a mixture of dimethyl formamide and acetonitrile (about 1 mL) containing fluorophilic acetate-protected DTBZ tosylate 44 (2 mg) is added and the vial is sealed. The reaction mixture is stirred and heated at 100° C. for 10 minutes and then is cooled to room temperature. The product mixture comprising the starting tosylate 44 and the intermediate F-18 alpha-fluoroalkyl protected dihydrotetrabenazine is diluted with water (10 mL) and applied to a Sep-Pak cartridge. The cartridge is then washed with water (3×) to remove unreacted fluoride ion and other water soluble components of the product mixture. The radiolabled PET imaging agent 45 and starting tosylate 44 are then eluted from the cartridge with acetonitrile. Most of the acetonitrile is then evaporated and the residue is dissolved in acetonitrile, filtered and subjected to preparative reverse phase HPLC to afford an aqueous formulation comprising PET imaging agent 45. (Tosylate 44 may be prepared from compound dihydrotetrabenazine compound 23 by acetylation of the free hydroxy group at ring position-2 followed by deprotection of the t-butyldiphenylsilyl (TBDPS) group and tosylation of the resultant primary alcohol.)

The foregoing examples are merely illustrative, serving to illustrate only some of the features of the invention. The appended claims are intended to claim the invention as broadly as it has been conceived and the examples herein presented are illustrative of selected embodiments from a manifold of all possible embodiments. Accordingly, it is the Applicants' intention that the appended claims are not to be limited by the choice of examples utilized to illustrate features of the present invention. As used in the claims, the word “comprises” and its grammatical variants logically also subtend and include phrases of varying and differing extent such as for example, but not limited thereto, “consisting essentially of” and “consisting of.” Where necessary, ranges have been supplied, those ranges are inclusive of all sub-ranges there between. It is to be expected that variations in these ranges will suggest themselves to a practitioner having ordinary skill in the art and where not already dedicated to the public, those variations should where possible be construed to be covered by the appended claims. It is also anticipated that advances in science and technology will make equivalents and substitutions possible that are not now contemplated by reason of the imprecision of language and these variations should also be construed where possible to be covered by the appended claims. 

1. An alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.
 2. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 1, comprising a fluorine-18 atom.
 3. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 1, comprising a fluorine-19 atom.
 4. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 1, which comprises a mixture of diastereomers.
 5. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 1, which is enantiomerically enriched.
 6. The enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 5 comprising a principal component enantiomer having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.
 7. The enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 6, which is at least 80% enantiomerically enriched.
 8. The enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 5, wherein R¹ is a C₅-C₁₀ fluoraliphatic radical and R² and R³ are methoxy groups.
 9. The enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 5, comprising a fluorine-18 atom.
 10. The enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 9, said compound being comprised in a formulation suitable for use in PET imaging.
 11. The enantiomerically enriched alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 5 comprising a principal component enantiomer having structure III

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.
 12. A PET imaging agent comprising an alpha-fluoroalkyl dihydrotetrabenazine compound having structure I

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and R⁴ is a C₁-C₁₀ aliphatic radical, a C₃-C₁₀ cycloaliphatic radical, or a C₃-C₁₀ aromatic radical.
 13. The PET imaging agent of claim 12 further comprising a salt of compound I.
 14. An alpha-fluoroalkyl dihydrotetrabenazine compound having structure II

wherein R¹ is a C₁-C₁₀ fluorinated aliphatic radical; R² is hydrogen or a C₁-C₁₀ aliphatic radical; R³ is hydrogen or a C₁-C₁₀ aliphatic radical; and the group —OR⁴ is selected from the group consisting of C₁-C₁₀ aliphatic esters, C₁-C₁₀ aliphatic ethers, and C₁-C₁₀ aliphatic carbamates.
 15. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14, comprising a fluorine-18 atom.
 16. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14, comprising a fluorine-19 atom.
 17. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14, wherein —OR⁴ is acetate.
 18. The alpha-fluoroalkyl dihdyrotetrabenazine compound according to claim 14, wherein —OR⁴ is methoxy.
 19. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14, wherein —OR⁴ is a carbamate group.
 20. The alpha-fluoroalkyl dihydrotetrabenazine compound according to claim 14, wherein the carbamate group is OCONH₂. 